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

doi:10.1016/j.ajhg.2016.11.013

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 EmmiFrancesco 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

Department of Medicine

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Abstract

© 2017 American Society of Human Genetics 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.

Original language	English
Pages (from-to)	64-74
Journal	American Journal of Human Genetics
Volume	100
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.11.013
Publication status	Published - 5 Jan 2017

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10.1016/j.ajhg.2016.11.013

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Carmona, F. D., Vaglio, A., Mackie, S. L., Hernández-Rodríguez, J., Monach, P. A., Castañeda, S., Solans, R., Morado, I. C., Narváez, J., Ramentol-Sintas, M., Pease, C. T., Dasgupta, B., Watts, R., Khalidi, N., Langford, C. A., Ytterberg, S., Boiardi, L., Beretta, L., Govoni, M., ... Fong, R. (2017). A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis. American Journal of Human Genetics, 100(1), 64-74. https://doi.org/10.1016/j.ajhg.2016.11.013

@article{4270c9d29fb74733af003ab0baa0103f,

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

abstract = "{\textcopyright} 2017 American Society of Human Genetics 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.",

author = "Carmona, {F. David} and Augusto Vaglio and Mackie, {Sarah L.} and Jos{\'e} Hern{\'a}ndez-Rodr{\'i}guez and Monach, {Paul A.} and Santos Casta{\~n}eda and Roser Solans and Morado, {Inmaculada C.} and Javier Narv{\'a}ez and Marc Ramentol-Sintas and Pease, {Colin T.} and Bhaskar Dasgupta and Richard Watts and Nader Khalidi and Langford, {Carol A.} and Steven Ytterberg and Luigi Boiardi and Lorenzo Beretta and Marcello Govoni and Giacomo Emmi and Francesco Bonatti and Cimmino, {Marco A.} and Torsten Witte and Thomas Neumann and Julia Holle and Verena Sch{\"o}nau and Laurent Sailler and Thomas Papo and Julien Haroche and Alfred Mahr and Luc Mouthon and {\O}yvind Molberg and Diamantopoulos, {Andreas P.} and Alexandre Voskuyl and Elisabeth Brouwer and Thomas Daikeler and Berger, {Christoph T.} and Molloy, {Eamonn S.} and Lorraine O'Neill and Daniel Blockmans and Lie, {Benedicte A.} and Paul Mclaren and Vyse, {Timothy J.} and Cisca Wijmenga and Yannick Allanore and Koeleman, {Bobby P.C.} and Callejas, {Jos{\'e} Luis} and Luis Caminal-Montero and Marc Corbera-Bellalta and {de Miguel}, Eugenio and L{\'o}pez, {J. Bernardino D{\'i}az} and Garc{\'i}a-Villanueva, {Mar{\'i}a Jes{\'u}s} and Carmen G{\'o}mez-Vaquero and Mercedes Guijarro-Rojas and Ana Hidalgo-Conde and Bego{\~n}a Mar{\'i}-Alfonso and Berriochoa, {Agust{\'i}n Mart{\'i}nez} and Zapico, {Aleida Mart{\'i}nez} and Mart{\'i}nez-Taboada, {V{\'i}ctor Manuel} and Miranda-Filloy, {Jos{\'e} A.} and Jordi Monfort and Norberto Ortego-Centeno and Mercedes P{\'e}rez-Conesa and Sergio Prieto-Gonz{\'a}lez and Enrique Raya and Fern{\'a}ndez, {Raquel R{\'i}os} and Julio S{\'a}nchez-Mart{\'i}n and Bernardo Sope{\~n}a and Laura T{\'i}o and Ainhoa Unzurrunzaga and Andrew Gough and Isaacs, {John D.} and Michael Green and Neil McHugh and Lesley Hordon and Sanjeet Kamath and Mohammed Nisar and Yusuf Patel and Yee, {Cee Seng} and Robert Stevens and Pradip Nandi and Anupama Nandagudi and Stephen Jarrett and Charles Li and Sarah Levy and Susan Mollan and Abdel Salih and Oliver Wordsworth and Emma Sanders and Esme Roads and Anne Gill and Lisa Carr and Christine Routledge and Karen Culfear and Asanka Nugaliyadde and Lynne James and Jenny Spimpolo and Andy Kempa and Felicity Mackenzie and Rosanna Fong",

year = "2017",

month = jan,

day = "5",

doi = "10.1016/j.ajhg.2016.11.013",

language = "English",

volume = "100",

pages = "64--74",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

Carmona, FD, Vaglio, A, Mackie, SL, Hernández-Rodríguez, J, Monach, PA, Castañeda, S, Solans, R, Morado, IC, Narváez, J, Ramentol-Sintas, M, Pease, CT, Dasgupta, B, Watts, R, Khalidi, N, Langford, CA, Ytterberg, S, Boiardi, L, Beretta, L, Govoni, M, Emmi, G, Bonatti, F, Cimmino, MA, Witte, T, Neumann, T, Holle, J, Schönau, V, Sailler, L, Papo, T, Haroche, J, Mahr, A, Mouthon, L, Molberg, Ø, Diamantopoulos, AP, Voskuyl, A, Brouwer, E, Daikeler, T, Berger, CT, Molloy, ES, O'Neill, L, Blockmans, D, Lie, BA, Mclaren, P, Vyse, TJ, Wijmenga, C, Allanore, Y, Koeleman, BPC, Callejas, JL, Caminal-Montero, L, Corbera-Bellalta, M, de Miguel, E, López, JBD, García-Villanueva, MJ, Gómez-Vaquero, C, Guijarro-Rojas, M, Hidalgo-Conde, A, Marí-Alfonso, B, Berriochoa, AM, Zapico, AM, Martínez-Taboada, VM, Miranda-Filloy, JA, Monfort, J, Ortego-Centeno, N, Pérez-Conesa, M, Prieto-González, S, Raya, E, Fernández, RR, Sánchez-Martín, J, Sopeña, B, Tío, L, Unzurrunzaga, A, Gough, A, Isaacs, JD, Green, M, McHugh, N, Hordon, L, Kamath, S, Nisar, M, Patel, Y, Yee, CS, Stevens, R, Nandi, P, Nandagudi, A, Jarrett, S, Li, C, Levy, S, Mollan, S, Salih, A, Wordsworth, O, Sanders, E, Roads, E, Gill, A, Carr, L, Routledge, C, Culfear, K, Nugaliyadde, A, James, L, Spimpolo, J, Kempa, A, Mackenzie, F & Fong, R 2017, 'A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis', American Journal of Human Genetics, vol. 100, no. 1, pp. 64-74. https://doi.org/10.1016/j.ajhg.2016.11.013

TY - JOUR

T1 - A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

AU - Carmona, F. David

AU - Vaglio, Augusto

AU - Mackie, Sarah L.

AU - Hernández-Rodríguez, José

AU - Monach, Paul A.

AU - Castañeda, Santos

AU - Solans, Roser

AU - Morado, Inmaculada C.

AU - Narváez, Javier

AU - Ramentol-Sintas, Marc

AU - Pease, Colin T.

AU - Dasgupta, Bhaskar

AU - Watts, Richard

AU - Khalidi, Nader

AU - Langford, Carol A.

AU - Ytterberg, Steven

AU - Boiardi, Luigi

AU - Beretta, Lorenzo

AU - Govoni, Marcello

AU - Emmi, Giacomo

AU - Bonatti, Francesco

AU - Cimmino, Marco A.

AU - Witte, Torsten

AU - Neumann, Thomas

AU - Holle, Julia

AU - Schönau, Verena

AU - Sailler, Laurent

AU - Papo, Thomas

AU - Haroche, Julien

AU - Mahr, Alfred

AU - Mouthon, Luc

AU - Molberg, Øyvind

AU - Diamantopoulos, Andreas P.

AU - Voskuyl, Alexandre

AU - Brouwer, Elisabeth

AU - Daikeler, Thomas

AU - Berger, Christoph T.

AU - Molloy, Eamonn S.

AU - O'Neill, Lorraine

AU - Blockmans, Daniel

AU - Lie, Benedicte A.

AU - Mclaren, Paul

AU - Vyse, Timothy J.

AU - Wijmenga, Cisca

AU - Allanore, Yannick

AU - Koeleman, Bobby P.C.

AU - Callejas, José Luis

AU - Caminal-Montero, Luis

AU - Corbera-Bellalta, Marc

AU - de Miguel, Eugenio

AU - López, J. Bernardino Díaz

AU - García-Villanueva, María Jesús

AU - Gómez-Vaquero, Carmen

AU - Guijarro-Rojas, Mercedes

AU - Hidalgo-Conde, Ana

AU - Marí-Alfonso, Begoña

AU - Berriochoa, Agustín Martínez

AU - Zapico, Aleida Martínez

AU - Martínez-Taboada, Víctor Manuel

AU - Miranda-Filloy, José A.

AU - Monfort, Jordi

AU - Ortego-Centeno, Norberto

AU - Pérez-Conesa, Mercedes

AU - Prieto-González, Sergio

AU - Raya, Enrique

AU - Fernández, Raquel Ríos

AU - Sánchez-Martín, Julio

AU - Sopeña, Bernardo

AU - Tío, Laura

AU - Unzurrunzaga, Ainhoa

AU - Gough, Andrew

AU - Isaacs, John D.

AU - Green, Michael

AU - McHugh, Neil

AU - Hordon, Lesley

AU - Kamath, Sanjeet

AU - Nisar, Mohammed

AU - Patel, Yusuf

AU - Yee, Cee Seng

AU - Stevens, Robert

AU - Nandi, Pradip

AU - Nandagudi, Anupama

AU - Jarrett, Stephen

AU - Li, Charles

AU - Levy, Sarah

AU - Mollan, Susan

AU - Salih, Abdel

AU - Wordsworth, Oliver

AU - Sanders, Emma

AU - Roads, Esme

AU - Gill, Anne

AU - Carr, Lisa

AU - Routledge, Christine

AU - Culfear, Karen

AU - Nugaliyadde, Asanka

AU - James, Lynne

AU - Spimpolo, Jenny

AU - Kempa, Andy

AU - Mackenzie, Felicity

AU - Fong, Rosanna

PY - 2017/1/5

Y1 - 2017/1/5

N2 - © 2017 American Society of Human Genetics 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.

AB - © 2017 American Society of Human Genetics 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.

U2 - 10.1016/j.ajhg.2016.11.013

DO - 10.1016/j.ajhg.2016.11.013

M3 - Article

SN - 0002-9297

VL - 100

SP - 64

EP - 74

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

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

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