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.

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Transcripción de la presentación:

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 Agustín Martínez- Berriochoa, Ainhoa Unzurrunzaga, Ana Hidalgo-Conde, Ana B. Madroñero-Vuelta, Antonio Fernández-Nebro, M. Carmen Ordóñez- Cañizares, Begoña Escalante, Begoña Marí-Alfonso, Bernardo Sopeña, César Magro, Enrique Raya, Elena Grau, José A. Román, Eugenio de Miguel, F. Javier 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 J. Alegre-Sancho, Luis Sáez-Comet, Mercedes Pérez-Conesa, Marc Corbera-Bellalta, M. Jesús García-Villanueva, M. Encarnación Fernández-Contreras, Olga Sanchez-Pernaute, Ricardo Blanco, Norberto Ortego-Centeno, Raquel Ríos-Fernández, José L. Callejas, Patricia Fanlo-Mateo, Víctor M. Martínez-Taboada, 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 H. Schirmer, Frank Moosig, Verena Schönau, Andre Franke, Øyvind Palm, Øyvind 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 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 Agustín Martínez-Berriochoa, Ainhoa Unzurrunzaga, Ana Hidalgo-Conde, Ana B. Madroñero-Vuelta, Antonio Fernández-Nebro, M. Carmen Ordóñez-Cañizares, Begoña Escalante, Begoña Marí-Alfonso, Bernardo Sopeña, César Magro, Enrique Raya, Elena Grau, José A. Román, Eugenio de Miguel, F. Javier 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 J. Alegre-Sancho, Luis Sáez-Comet, Mercedes Pérez-Conesa, Marc Corbera-Bellalta, M. Jesús García-Villanueva, M. Encarnación Fernández-Contreras, Olga Sanchez-Pernaute, Ricardo Blanco, Norberto Ortego-Centeno, Raquel Ríos-Fernández, José L. Callejas, Patricia Fanlo-Mateo, Víctor M. Martínez-Taboada, 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 H. Schirmer, Frank Moosig, Verena Schönau, Andre Franke, Øyvind Palm, Øyvind 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 The American Journal of Human Genetics Volume 96, Issue 4, Pages 565-580 (April 2015) DOI: 10.1016/j.ajhg.2015.02.009 Copyright © 2015 The Authors Terms and Conditions

Figure 1 Manhattan Plot Representation of the Immunochip Results The −log10 of the combined logistic regression test p values are plotted against their physical chromosomal position. The red line represents the genome-wide level of significance (p < 5 × 10−8), and the blue line represents the statistical significance for suggestive signals (p < 1 × 10−4). The most relevant associations are highlighted. The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions

Figure 2 Manhattan Plot Representation of the Step-wise Conditional Logistic Regression of the HLA Region (A) Unconditioned test of the HLA region. (B) Results of the HLA region after conditioning to HLA-DRβ1 His13. (C) Results of the HLA region after conditioning to HLA-DRβ1 His13 and HLA-DQα1 Gly56. (D) Results of the HLA region after conditioning to HLA-DRβ1 His13, HLA-DQα1 Gly56, and HLA-B Thr45. The −log10 of the combined logistic regression test p values are plotted against their physical chromosomal position. A red/blue color gradient was used to represent the effect size of each analyzed variant (red for risk and blue for protection). The red line represents the genome-wide level of significance (p < 5 × 10−8). The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions

Figure 3 Haplotypes Observed in Our Dataset between the Residues of the Class II Positions of the Model that Best Explains the Association of This Genomic Region with Giant Cell Arteritis (A) Graphical representation of the four haplotypes formed by the amino acids of the DQα1 positions 47, 56, and 76. The frequency of every amino acid is shown in brackets. (B) Each row refers to the haplotype of one HLA-DRβ1 13 amino acid and one HLA-DQα1 haplotype. Haplotype frequencies of case subjects (red) and control subjects (blue), odds ratios (OR), and −log10 of the logistic regression test p values are plotted. A red/blue color gradient was used in the OR bars to represent the effect size of each analyzed variant (red for risk and blue for protection). The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions

Figure 4 Regional Plots of the Three Most Associated Loci with GCA outside the HLA Region in the Overall Meta-analysis after Imputation (A) Protein tyrosine phosphatase non-receptor type 22 (PTPN22) region. (B) v-rel avian reticuloendotheliosis viral oncogene homolog (REL) region. (C) Leucine-rich repeat containing 32 (LRRC32) region. (D) Results for the LRRC32 region after conditioning for the lead SNP (rs10160518). Red arrows point to the lead variants (highlighted in violet). The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions

Figure 5 Distributions of Genetic Risk Score Predictive for Susceptibility to Develop Rheumatoid Arthritis by Disease Status (A, C, and E) Histogram of genetic risk scores calculated with all the RA alleles (A), with non-HLA alleles only (C), or with HLA alleles only (E). (B, D, and F) Distribution curve of genetic risk scores calculated with all the RA alleles (B), with non-HLA alleles only (D), or with HLA alleles only (F). The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions

Figure 6 Ribbon Representation of the HLA Molecules HLA-DR, HLA-DQ, and HLA-B/β2 Microglobulin The amino acid positions of the HLA model associated with GCA are highlighted in orange. The American Journal of Human Genetics 2015 96, 565-580DOI: (10.1016/j.ajhg.2015.02.009) Copyright © 2015 The Authors Terms and Conditions