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Five genes identified that play major role in Takayasu arteritis

Researchers have uncovered the genetics behind what makes some people susceptible to Takayasu arteritis, a debilitating disease that can lead to poor circulation, easy tiredness in the legs and arms, organ damage and stroke.

A study led by the University of Michigan has identified five genes tied to Takayasu arteritis, an inflammation that damages the aorta and can lead to narrowed arteries, aneurysms, high blood pressure, and heart failure. The findings appear in the August issue of The American Journal of Human Genetics.

“Discovering the genetic makeup of Takayasu arteritis is a pivotal step that will lead to fundamental understanding of the disease mechanisms and developing therapies to more effectively treat it,” says senior author Amr Sawalha, M.D., associate professor of internal medicine in the division of rheumatology at the U-M Medical School. “This disease can be devastating but is understudied and poorly understood.”

Takayasu arteritis mainly causes inflammation in the aorta – the large artery that carries blood from the heart to body – and other major blood vessels. This inflammation can also affect the heart valves, reduce blood flow to the legs and arms, and cause a stroke. Other symptoms include weight loss, fever, night sweats, fatigue and joint and muscle pain.

The disease is most common among women and typically occurs between the ages 20 and 40.

The new findings increase the number of genes linked to susceptibility to the disease to five risk areas both in the HLA (an inherited group of genes known as human leukocyte antigen) and outside the HLA. In addition to the previously established genetic association in HLA-B for Takayasu arteritis, researchers discovered and carefully localized novel genetic risk areas in HLA-DQB1/HLA-DRB1, FCGR2A/FCGR3A, and PSMG1.

“We have established and localized the genetic association with IL12B, which encodes the P40 subunit of the interleukin-12 (IL-12) and IL-23,” says Güher Saruhan-Direskeneli, M.D., professor of physiology at Istanbul University and co-author of the study.

“Therapies to inhibit the IL12/IL23 pathway have been successful in other inflammatory diseases, and these recent findings support investigating this pathway closer in Takayasu arteritis as a potential therapeutic target,” Sawalha adds.


Additional authors: Travis Hughes, Kenan Aksu, Gokhan Keser, Patrick Coit, Sibel Z. Aydin,Fatma Alibaz-Oner, Sevil Kamalı, Murat Inanc, Simon Carette, Gary S. Hoffman, Servet Akar, Fatos Onen, Nurullah Akkoc, Nader A. Khalidi, Curry Koening, Omer Karadag, Sedat Kiraz, Carol A. Langford, Carol A. McAlear, Zeynep Ozbalkan, Askin Ates,Yasar Karaaslan, Kathleen Maksimowicz-McKinnon, Paul A. Monach, Hu¨seyin T. Ozer, Emire Seyahi, Izzet Fresko, Ayse Cefle, Philip Seo, Kenneth J. Warrington, Mehmet A. Ozturk, Steven R. Ytterberg, Veli Cobankara, A. Mesut Onat, Joel M. Guthridge, Judith A. James, Ercan Tunc, Nursxen Duzgun, Muge Bıcakcıgil, Sibel P. Yentu¨r, Peter A. Merkel, Haner Direskeneli.

Disclosures: None

Funding: This work was made possible by funding from the University of Michigan, the Vasculitis Foundation, and the National Institutes of Health.

Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis,” American Journal of Human Genetics, August, 2013, doi:10.1016/j.ajhg.2013.05.026

Güher Saruhan-Direskeneli1, Travis Hughes2, Kenan Aksu3, Gokhan Keser3, Patrick Coit2, Sibel Z. Aydin4, 5, Fatma Alibaz-Oner4, Sevil Kamalı6, Murat Inanc6, Simon Carette7, Gary S. Hoffman8, Servet Akar9, Fatos Onen9, Nurullah Akkoc9, Nader A. Khalidi10, Curry Koening11, Omer Karadag12, Sedat Kiraz12, Carol A. Langford8, Carol A. McAlear13, Zeynep Ozbalkan14, Askin Ates14, 15, Yasar Karaaslan14, 16, Kathleen Maksimowicz-McKinnon17, 18, Paul A. Monach19, Hüseyin T. Ozer20, Emire Seyahi21, Izzet Fresko21, Ayse Cefle22, Philip Seo23, Kenneth J. Warrington24, Mehmet A. Ozturk25, Steven R. Ytterberg24, Veli Cobankara26, A. Mesut Onat27, Joel M. Guthridge28, Judith A. James28, Ercan Tunc29, Nurşen Duzgun15, Muge Bıcakcıgil30, Sibel P. Yentür1, Peter A. Merkel13, Haner Direskeneli4 and Amr H. Sawalha2*

  1. Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey
  2. Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA
  3. Department of Rheumatology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
  4. Department of Rheumatology, Faculty of Medicine, Marmara University, Istanbul, 34890, Turkey
  5. Unit of Rheumatology, Goztepe Training and Research Hospital, Medeniyet University, Istanbul 34730, Turkey
  6. Department of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey
  7. Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5L 3L9, Canada
  8. Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH 44195, USA
  9. Department of Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey
  10. Division of Rheumatology, St. Joseph’s Healthcare, McMaster University, Hamilton, ON L8N 1Y2, Canada
  11. Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA
  12. Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
  13. Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA
  14. Department of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey
  15. Department of Rheumatology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey
  16. Department of Rheumatology, Faculty of Medicine, Hitit University, Çorum 19200, Turkey
  17. Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA 15261, USA
  18. Division of Rheumatology, Henry Ford Health System, Detroit, MI 48202, USA
  19. Section of Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA
  20. Department of Rheumatology, Faculty of Medicine, Cukurova University, Adana 01330, Turkey
  21. Department of Rheumatology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey
  22. Department of Rheumatology, Faculty of Medicine, Kocaeli University, Kocaeli 41380, Turkey
  23. Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA
  24. Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
  25. Department of Rheumatology, Faculty of Medicine, Gazi University, Ankara 06500, Turkey
  26. Department of Rheumatology, Faculty of Medicine, Pamukkale University, Denizli 20160, Turkey
  27. Department of Rheumatology, Faculty of Medicine, Gaziantep University, Gaziantep 27310, Turkey
  28. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
  29. Department of Rheumatology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey
  30. Department of Rheumatology, Faculty of Medicine, Yeditepe University, Istanbul 34752, Turkey

Corresponding author*

University of Michigan Health System