A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis F. David Carmona, Augusto Vaglio,

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Transcripción de la presentación:

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis F. David Carmona, Augusto Vaglio, Sarah L. Mackie, José Hernández-Rodríguez, Paul A. Monach, Santos Castañeda, Roser Solans, Inmaculada C. Morado, Javier Narváez, Marc Ramentol-Sintas, Colin T. Pease, Bhaskar Dasgupta, Richard Watts, Nader Khalidi, Carol A. Langford, Steven Ytterberg, Luigi Boiardi, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Francesco Bonatti, Marco A. Cimmino, Torsten Witte, Thomas Neumann, Julia Holle, Verena Schönau, Laurent Sailler, Thomas Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P. Diamantopoulos, Alexandre Voskuyl, Elisabeth Brouwer, Thomas Daikeler, Christoph T. Berger, Eamonn S. Molloy, Lorraine O’Neill, Daniel Blockmans, Benedicte A. Lie, Paul Mclaren, Timothy J. Vyse, Cisca Wijmenga, Yannick Allanore, Bobby P.C. Koeleman José Luis Callejas, 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, Víctor Manuel Martínez-Taboada, José A. Miranda-Filloy, Jordi Monfort, Norberto Ortego-Centeno, Mercedes Pérez-Conesa, Sergio Prieto-González, Enrique Raya, Raquel Ríos Fernández, Julio Sánchez- Martín, Bernardo Sopeña, Laura Tío, Ainhoa Unzurrunzaga Andrew Gough, John D. Isaacs, Michael Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Cee-Seng Yee, Robert Stevens, Pradip Nandi, Anupama Nandagudi, Stephen Jarrett, Charles Li, Sarah Levy, Susan 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 Haroon Rashid, James I. Robinson, Mike Morgan, Louise Sorensen, John Taylor Simon Carette, Sharon Chung, David Cuthbertson, Lindsy J. Forbess, Ora Gewurz-Singer, Gary S. Hoffman, Curry L. Koening, Kathleen M. Maksimowicz-McKinnon, Carol A. McAlear, Larry W. Moreland, Christian Pagnoux, Philip Seo, Ulrich Specks, Robert F. Spiera, Antoine Sreih, Kenneth J. Warrington, Michael Weisman, Jennifer H. Barrett, María C. Cid, Carlo Salvarani, Peter A. Merkel, Ann W. Morgan, Miguel A. González-Gay, Javier Martín F. David Carmona, Augusto Vaglio, Sarah L. Mackie, José Hernández-Rodríguez, Paul A. Monach, Santos Castañeda, Roser Solans, Inmaculada C. Morado, Javier Narváez, Marc Ramentol-Sintas, Colin T. Pease, Bhaskar Dasgupta, Richard Watts, Nader Khalidi, Carol A. Langford, Steven Ytterberg, Luigi Boiardi, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Francesco Bonatti, Marco A. Cimmino, Torsten Witte, Thomas Neumann, Julia Holle, Verena Schönau, Laurent Sailler, Thomas Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P. Diamantopoulos, Alexandre Voskuyl, Elisabeth Brouwer, Thomas Daikeler, Christoph T. Berger, Eamonn S. Molloy, Lorraine O’Neill, Daniel Blockmans, Benedicte A. Lie, Paul Mclaren, Timothy J. Vyse, Cisca Wijmenga, Yannick Allanore, Bobby P.C. Koeleman José Luis Callejas, 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, Víctor Manuel Martínez-Taboada, José A. Miranda-Filloy, Jordi Monfort, Norberto Ortego-Centeno, Mercedes Pérez-Conesa, Sergio Prieto-González, Enrique Raya, Raquel Ríos Fernández, Julio Sánchez- Martín, Bernardo Sopeña, Laura Tío, Ainhoa Unzurrunzaga Andrew Gough, John D. Isaacs, Michael Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Cee-Seng Yee, Robert Stevens, Pradip Nandi, Anupama Nandagudi, Stephen Jarrett, Charles Li, Sarah Levy, Susan 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 Haroon Rashid, James I. Robinson, Mike Morgan, Louise Sorensen, John Taylor Simon Carette, Sharon Chung, David Cuthbertson, Lindsy J. Forbess, Ora Gewurz-Singer, Gary S. Hoffman, Curry L. Koening, Kathleen M. Maksimowicz-McKinnon, Carol A. McAlear, Larry W. Moreland, Christian Pagnoux, Philip Seo, Ulrich Specks, Robert F. Spiera, Antoine Sreih, Kenneth J. Warrington, Michael Weisman, Jennifer H. Barrett, María C. Cid, Carlo Salvarani, Peter A. Merkel, Ann W. Morgan, Miguel A. González-Gay, Javier Martín F. David Carmona, Augusto Vaglio, Sarah L. Mackie, José Hernández-Rodríguez, Paul A. Monach, Santos Castañeda, Roser Solans, Inmaculada C. Morado, Javier Narváez, Marc Ramentol-Sintas, Colin T. Pease, Bhaskar Dasgupta, Richard Watts, Nader Khalidi, Carol A. Langford, Steven Ytterberg, Luigi Boiardi, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Francesco Bonatti, Marco A. Cimmino, Torsten Witte, Thomas Neumann, Julia Holle, Verena Schönau, Laurent Sailler, Thomas Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P. Diamantopoulos, Alexandre Voskuyl, Elisabeth Brouwer, Thomas Daikeler, Christoph T. Berger, Eamonn S. Molloy, Lorraine O’Neill, Daniel Blockmans, Benedicte A. Lie, Paul Mclaren, Timothy J. Vyse, Cisca Wijmenga, Yannick Allanore, Bobby P.C. Koeleman José Luis Callejas, 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, Víctor Manuel Martínez-Taboada, José A. Miranda-Filloy, Jordi Monfort, Norberto Ortego-Centeno, Mercedes Pérez-Conesa, Sergio Prieto-González, Enrique Raya, Raquel Ríos Fernández, Julio Sánchez- Martín, Bernardo Sopeña, Laura Tío, Ainhoa Unzurrunzaga Andrew Gough, John D. Isaacs, Michael Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Cee-Seng Yee, Robert Stevens, Pradip Nandi, Anupama Nandagudi, Stephen Jarrett, Charles Li, Sarah Levy, Susan 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 Haroon Rashid, James I. Robinson, Mike Morgan, Louise Sorensen, John Taylor Simon Carette, Sharon Chung, David Cuthbertson, Lindsy J. Forbess, Ora Gewurz-Singer, Gary S. Hoffman, Curry L. Koening, Kathleen M. Maksimowicz-McKinnon, Carol A. McAlear, Larry W. Moreland, Christian Pagnoux, Philip Seo, Ulrich Specks, Robert F. Spiera, Antoine Sreih, Kenneth J. Warrington, Michael Weisman, Jennifer H. Barrett, María C. Cid, Carlo Salvarani, Peter A. Merkel, Ann W. Morgan, Miguel A. González-Gay, Javier Martín F. David Carmona, Augusto Vaglio, Sarah L. Mackie, José Hernández-Rodríguez, Paul A. Monach, Santos Castañeda, Roser Solans, Inmaculada C. Morado, Javier Narváez, Marc Ramentol-Sintas, Colin T. Pease, Bhaskar Dasgupta, Richard Watts, Nader Khalidi, Carol A. Langford, Steven Ytterberg, Luigi Boiardi, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Francesco Bonatti, Marco A. Cimmino, Torsten Witte, Thomas Neumann, Julia Holle, Verena Schönau, Laurent Sailler, Thomas Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P. Diamantopoulos, Alexandre Voskuyl, Elisabeth Brouwer, Thomas Daikeler, Christoph T. Berger, Eamonn S. Molloy, Lorraine O’Neill, Daniel Blockmans, Benedicte A. Lie, Paul Mclaren, Timothy J. Vyse, Cisca Wijmenga, Yannick Allanore, Bobby P.C. Koeleman José Luis Callejas, 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, Víctor Manuel Martínez-Taboada, José A. Miranda-Filloy, Jordi Monfort, Norberto Ortego-Centeno, Mercedes Pérez-Conesa, Sergio Prieto-González, Enrique Raya, Raquel Ríos Fernández, Julio Sánchez- Martín, Bernardo Sopeña, Laura Tío, Ainhoa Unzurrunzaga Andrew Gough, John D. Isaacs, Michael Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Cee-Seng Yee, Robert Stevens, Pradip Nandi, Anupama Nandagudi, Stephen Jarrett, Charles Li, Sarah Levy, Susan 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 Haroon Rashid, James I. Robinson, Mike Morgan, Louise Sorensen, John Taylor Simon Carette, Sharon Chung, David Cuthbertson, Lindsy J. Forbess, Ora Gewurz-Singer, Gary S. Hoffman, Curry L. Koening, Kathleen M. Maksimowicz-McKinnon, Carol A. McAlear, Larry W. Moreland, Christian Pagnoux, Philip Seo, Ulrich Specks, Robert F. Spiera, Antoine Sreih, Kenneth J. Warrington, Michael Weisman, Jennifer H. Barrett, María C. Cid, Carlo Salvarani, Peter A. Merkel, Ann W. Morgan, Miguel A. González-Gay, Javier Martín The American Journal of Human Genetics Volume 100, Issue 1, Pages 64-74 (January 2017) DOI: 10.1016/j.ajhg.2016.11.013 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Manhattan Plot Representation of the GWAS Results The −log10 of the inverse variance-weighted meta-analysis p values are plotted against their physical chromosomal position. The red line represents the genome-wide level of significance (p < 5 × 10−8). The most relevant associations are highlighted. The American Journal of Human Genetics 2017 100, 64-74DOI: (10.1016/j.ajhg.2016.11.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Regional Plots of the Associated Loci with GCA outside the HLA Region in the Overall Meta-analysis (A) Plasminogen (PLG) region. (B) Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) region. Lead variants are highlighted in violet. The American Journal of Human Genetics 2017 100, 64-74DOI: (10.1016/j.ajhg.2016.11.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Interaction Network Formed for GCA Risk Loci GWAS genes of this study and those previously identified through Immunochip and consistent candidate gene studies were included in the analysis. STRING database was used to look for both direct and indirect interactions among selected genes. The width of the blue lines indicates the reliability of each interaction. The American Journal of Human Genetics 2017 100, 64-74DOI: (10.1016/j.ajhg.2016.11.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions