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 Karadag; 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

doi:10.1016/j.ajhg.2020.11.014

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

Am J Hum Genet. 2021 Jan 7;108(1):84-99. doi: 10.1016/j.ajhg.2020.11.014. Epub 2020 Dec 11.

Authors

Lourdes Ortiz-Fernández¹, Güher Saruhan-Direskeneli², Fatma Alibaz-Oner³, Sema Kaymaz-Tahra³, Patrick Coit⁴, Xiufang Kong⁵, Allan P Kiprianos⁶, Robert T Maughan⁶, Sibel Z Aydin⁷, Kenan Aksu⁸, Gokhan Keser⁸, Sevil Kamali⁹, Murat Inanc⁹, Jason Springer¹⁰, Servet Akar¹¹, Fatos Onen¹², Nurullah Akkoc¹³, Nader A Khalidi¹⁴, Curry Koening¹⁵, Omer Karadag¹⁶, Sedat Kiraz¹⁶, Lindsy Forbess¹⁷, Carol A Langford¹⁸, Carol A McAlear¹⁹, Zeynep Ozbalkan²⁰, Sule Yavuz²¹, Gozde Yildirim Çetin²², Nilufer Alpay-Kanitez²³, Sharon Chung²⁴, Askin Ates²⁵, Yasar Karaaslan²⁶, Kathleen McKinnon-Maksimowicz²⁷, Paul A Monach²⁸, Hüseyin T E Ozer²⁹, Emire Seyahi³⁰, Izzet Fresko³⁰, Ayse Cefle³¹, Philip Seo³², Kenneth J Warrington³³, Mehmet A Ozturk³⁴, Steven R Ytterberg³³, Veli Cobankara³⁵, Ahmet Mesut Onat³⁶, Nurşen Duzgun³⁷, Muge Bıcakcıgil³⁸, Sibel P Yentür², Lindsay Lally³⁹, Angelo A Manfredi⁴⁰, Elena Baldissera⁴⁰, Eren Erken²⁹, Ayten Yazici³¹, Bünyamin Kısacık³⁶, Timuçin Kaşifoğlu⁴¹, Ediz Dalkilic⁴², David Cuthbertson⁴³, Christian Pagnoux⁴⁴, Antoine Sreih¹⁹, Guillermo Reales⁴⁵, Chris Wallace⁴⁶, Jonathan D Wren⁴⁷, Deborah S Cunninghame-Graham⁴⁸, Timothy J Vyse⁴⁸, Ying Sun⁵, Huiyong Chen⁵, Peter C Grayson⁴⁹, Enrico Tombetti⁵⁰, Lindi Jiang⁵¹, Justin C Mason⁶, Peter A Merkel⁵², Haner Direskeneli³, Amr H Sawalha⁵³

Affiliations

¹ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
² Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul 34093, Turkey.
³ Department of Internal Medicine, Division of Rheumatology, Marmara University, Faculty of Medicine, Istanbul 34890, Turkey.
⁴ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁶ National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
⁷ Department of Internal Medicine, Division of Rheumatology, Marmara University, Faculty of Medicine, Istanbul 34890, Turkey; Faculty of Medicine, Division of Rheumatology, the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1Y 4E9, Canada.
⁸ Department of Internal Medicine, Division of Rheumatology, Ege University, Faculty of Medicine, Izmir 35100, Turkey.
⁹ Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul 34903, Turkey.
¹⁰ Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
¹¹ Department of Internal Medicine, Division of Rheumatology, Katip Çelebi University, Faculty of Medicine, İzmir 35620, Turkey; Department of Internal Medicine, Division of Rheumatology, Dokuz Eylül University, Faculty of Medicine, Izmir 35340, Turkey.
¹² Department of Internal Medicine, Division of Rheumatology, Dokuz Eylül University, Faculty of Medicine, Izmir 35340, Turkey.
¹³ Department of Internal Medicine, Division of Rheumatology, Dokuz Eylül University, Faculty of Medicine, Izmir 35340, Turkey; Department of Internal Medicine, Division of Rheumatology, Celal Bayar University, Faculty of Medicine, Manisa 45140, Turkey.
¹⁴ Division of Rheumatology, St. Joseph's Healthcare, McMaster University, Hamilton, ON L8N 1Y2, Canada.
¹⁵ Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA.
¹⁶ Department of Internal Medicine, Division of Rheumatology, Hacettepe University, Faculty of Medicine, Ankara 06100, Turkey.
¹⁷ Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁸ Department of Rheumatology, Cleveland Clinic, Cleveland, OH 44195, USA.
¹⁹ Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
²⁰ Department of Internal Medicine, Division of Rheumatology, Hitit University, Faculty of Medicine, Çorum 19200, Turkey; Department of Internal Medicine, Division of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey.
²¹ Division of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala 751 85, Sweden.
²² Department of Internal Medicine, Division of Rheumatology, Sutcu Imam University, Faculty of Medicine, Kahramanmaraş 46050, Turkey.
²³ Department of Internal Medicine, Division of Rheumatology, Koc University, Faculty of Medicine, Istanbul 34450, Turkey.
²⁴ Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁵ Department of Internal Medicine, Division of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey; Department of Internal Medicine, Division of Rheumatology, Ankara University, Faculty of Medicine, Ankara 06100, Turkey.
²⁶ Department of Internal Medicine, Division of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey.
²⁷ Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Rheumatology, Henry Ford Health System, Detroit, MI 48202, USA.
²⁸ Section of Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA.
²⁹ Department of Internal Medicine, Division of Rheumatology, Cukurova University, Faculty of Medicine, Adana 01330, Turkey.
³⁰ Department of Internal Medicine, Division of Rheumatology, Istanbul University-Cerrahpaşa, Faculty of Medicine, Istanbul 34098, Turkey.
³¹ Department of Internal Medicine, Division of Rheumatology, Kocaeli University, Faculty of Medicine, Kocaeli 41380, Turkey.
³² Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
³³ Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
³⁴ Department of Internal Medicine, Division of Rheumatology, Gazi University, Faculty of Medicine, Ankara 06500, Turkey.
³⁵ Department of Internal Medicine, Division of Rheumatology, Pamukkale University, Faculty of Medicine, Denizli 20160, Turkey.
³⁶ Division of Rheumatology, Gaziantep Medical Park Hospital, Gaziantep 27060, Turkey; Department of Internal Medicine, Division of Rheumatology, Gaziantep University, Faculty of Medicine, Gaziantep 27310, Turkey.
³⁷ Department of Internal Medicine, Division of Rheumatology, Ankara University, Faculty of Medicine, Ankara 06100, Turkey.
³⁸ Department of Internal Medicine, Division of Rheumatology, Yeditepe University, Faculty of Medicine, Istanbul 34752, Turkey.
³⁹ Department of Medicine, Division of Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA.
⁴⁰ Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Hospital, Milan 20132, Italy.
⁴¹ Department of Internal Medicine, Division of Rheumatology, Osman Gazi University, Faculty of Medicine, Eskişehir 26030, Turkey.
⁴² Department of Internal Medicine, Division of Rheumatology, Uludag University, Faculty of Medicine, Bursa 16059, Turkey.
⁴³ Department of Biostatistics, University of South Florida, Tampa, FL 33612, USA.
⁴⁴ Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5L 3L9, Canada.
⁴⁵ Cambridge Institute of Therapeutic Immunology & Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
⁴⁶ Cambridge Institute of Therapeutic Immunology & Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
⁴⁷ Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁴⁸ Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK.
⁴⁹ Systemic Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
⁵⁰ Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Hospital, Milan 20132, Italy; Department of Biomedical and Clinical Sciences L. Sacco, Milan University, Milan 20157, Italy.
⁵¹ Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Evidence-Based Medicine Center, Fudan University, Shanghai 200032, China.
⁵² Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵³ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: asawalha@pitt.edu.

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.

Keywords: GWAS; HLA; Takayasu arteritis; chromatin interaction; eQTL; epigenetic; genetic association; genetic risk scroe; vasculitis.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods
Humans
Inflammatory Bowel Diseases / genetics
Male
Polymorphism, Single Nucleotide / genetics
Takayasu Arteritis / genetics*

Abstract

Publication types

MeSH terms

Grants and funding