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

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• 作者：F. David Carmona¹ ; ² ; ^{dcarmona@ipb.csic.es} ; Augusto Vaglio³ ; Sarah L. Mackie⁴ ; José ; Herná ; ndez-Rodrí ; guez⁵ ; Paul A. Monach⁶ ; Santos Castañ ; eda⁷ ; Roser Solans⁸ ; Inmaculada C. Morado⁹ ; Javier Narvá ; ez¹⁰ ; Marc Ramentol-Sintas⁸ ; Colin T. Pease⁴ ; Bhaskar Dasgupta¹¹ ; Richard Watts¹² ; Nader Khalidi¹³ ; Carol A. Langford¹⁴ ; Steven Ytterberg¹⁵ ; Luigi Boiardi¹⁶ ; Lorenzo Beretta¹⁷ ; Marcello Govoni¹⁸ ; Giacomo Emmi¹⁹ ; Francesco Bonatti²⁰ ; Marco A. Cimmino²¹ ; Torsten Witte²² ; Thomas Neumann²³ ; Julia Holle²⁴ ; Verena Schö ; nau²⁵ ; Laurent Sailler²⁶ ; Thomas Papo²⁷ ; Julien Haroche²⁸ ; Alfred Mahr²⁹ ; Luc Mouthon³⁰ ; Ø ; yvind Molberg³¹ ; Andreas P. Diamantopoulos³² ; Alexandre Voskuyl³³ ; Elisabeth Brouwer³⁴ ; Thomas Daikeler³⁵ ; Christoph T. Berger³⁶ ; Eamonn S. Molloy³⁷ ; Lorraine O&rsquo ; Neill³⁷ ; Daniel Blockmans³⁸ ; Benedicte A. Lie³⁹ ; Paul Mclaren⁴⁰ ; Timothy J. Vyse⁴¹ ; Cisca Wijmenga⁴² ; Yannick Allanore⁴³ ; Bobby P.C. Koeleman⁴⁴ ; Spanish CGA Group José ; Luis Callejas ; Luis Caminal-Montero ; Marc Corbera-Bellalta ; Eugenio de Miguel ; J. Bernardino Dí ; az Ló ; pez ; Marí ; a Jesú ; s Garcí ; a-Villanueva ; Carmen Gó ; mez-Vaquero ; Mercedes Guijarro-Rojas ; Ana Hidalgo-Conde ; Begoñ ; a Marí ; -Alfonso ; Agustí ; n Martí ; nez Berriochoa ; Aleida Martí ; nez Zapico ; Ví ; ctor Manuel Martí ; nez-Taboada ; José ; A. Miranda-Filloy ; Jordi Monfort ; Norberto Ortego-Centeno ; Mercedes Pé ; rez-Conesa ; Sergio Prieto-Gonzá ; lez ; Enrique Raya ; Raquel Rí ; os Ferná ; ndez ; Julio Sá ; nchez-Martí ; n ; Bernardo Sopeñ ; a ; Laura Tí ; o ; Ainhoa Unzurrunzaga
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：5 January 2017
• 年：2017
• 卷：100
• 期：1
• 页码：64-74
• 全文大小：977 K
• 卷排序：100

文摘

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.