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

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 KaradagSedat 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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)84-99
Number of pages16
JournalAmerican journal of human genetics
Volume108
Issue number1
DOIs
StatePublished - Jan 7 2021

Keywords

  • chromatin interaction
  • epigenetic
  • eQTL
  • genetic association
  • genetic risk scroe
  • GWAS
  • HLA
  • Takayasu arteritis
  • vasculitis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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