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Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

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Lourdes Ortiz-Fernández, Güher Saruhan-Direskeneli, Fatma Alibaz-Oner, Sema Kaymaz-Tahra, Patrick Coit, Xiufang Kong, Allan P. Kiprianos, Robert T. Maughan, Sibel Z. Aydin, Kenan Aksu, Gokhan Keser, Sevil Kamali, Murat Inanc, Jason Springer, Servet Akar, Fatos Onen, Nurullah Akkoc, Nader A. Khalidi, Curry Koening, Omer Karadag & 51 more Sedat Kiraz, Lindsy Forbess, Carol A. Langford, Carol A. McAlear, Zeynep Ozbalkan, Sule Yavuz, Gozde Yildirim Çetin, Nilufer Alpay-Kanitez, Sharon Chung, Askin Ates, Yasar Karaaslan, Kathleen McKinnon-Maksimowicz, Paul A. Monach, Hüseyin T.E. Ozer, Emire Seyahi, Izzet Fresko, Ayse Cefle, Philip Seo, Kenneth J. Warrington, Mehmet A. Ozturk, Steven R. Ytterberg, Veli Cobankara, Ahmet Mesut Onat, Nurşen Duzgun, Muge Bıcakcıgil, Sibel P. Yentür, Lindsay Lally, Angelo A. Manfredi, Elena Baldissera, Eren Erken, Ayten Yazici, Bünyamin Kısacık, Timuçin Kaşifoğlu, Ediz Dalkilic, David Cuthbertson, Christian Pagnoux, Antoine Sreih, Guillermo Reales, Chris Wallace, Jonathan D. Wren, Deborah S. Cunninghame-Graham, Timothy J. Vyse, Ying Sun, Huiyong Chen, Peter C. Grayson, Enrico Tombetti, Lindi Jiang, Justin C. Mason, Peter A. Merkel, Haner Direskeneli, Amr H. Sawalha

Original languageEnglish
Pages (from-to)84-99
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number1
Published7 Jan 2021

Bibliographical note

Funding Information: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant R01 AR070148 to A.H.S. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( U54 AR057319 and U01 AR51874 04 ), the National Center for Research Resources ( U54 RR019497 ), and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences . J.C.M., A.P.K., and R.M.M. acknowledge support from the Imperial College, National Institute for Health Research, Biomedical Research Centre . C.W. and G.R. acknowledge support from The Wellcome Trust ( WT107881 ) and the Medical Research Council ( MC_UU_00002/4 ). This work was supported by the use of study data downloaded from the dbGaP website, under dbGaP: phs000272.v1.p1, phs000431.v2.p1, phs000583.v1.p1, and phs000444.v1.p1. Publisher Copyright: © 2020 American Society of Human Genetics Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10−5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

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