Clarification of pathophysiology of Takayasu Arteritis

• Project/Area Number: 25860809
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kyoto University
• Principal Investigator: TERAO Chikashi 京都大学, 医学(系)研究科(研究院), 助教 (60610459)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 自己免疫性疾患 / 高安動脈炎 / 全ゲノム関連解析 / ゲノム関連解析 / 疾患感受性遺伝子 / 治療標的

Outline of Final Research Achievements

We collected DNA samples and clinical information from more than 400 patients with Takayasu arteritis (TAK). We identified a novel susceptibility HLA-B allele and two novel non-HLA susceptibility loci. The top SNP in the IL12B region showed high odds ratio and was associated with complication and severity of aortic regurgitation, a severe complication of TAK. Furthermore, the SNP demonstrated a synergistic effect with HLA-B*52:01, the strongest HLA susceptibility allele to TAK. These results indicate that IL12p40, encoded by IL12B, is a key molecule to TAK. Furthermore, we showed that 6.4% of patients with TAK suffered from ulcerative colitis (UC), one of inflammatory bowel diseases (IBD). We also showed a significant genetic overlap between TAK and UC, suggesting that the two diseases share common molecular pathways. Furthermore, we showed that ustekinumab, a monoclonal antibody to IL12p40 used for patients with IBD, was effective to patients with TAK in a pilot clinical study.

Research Products

• [Journal Article] Takayasu arteritis and ulcerative colitis -high concurrence ratio and genetic overlap (2015)
  • Author(s): Terao C, Matsumura T, Yoshifuji H et al.
  • Journal Title: Arthritis and Rheumatology Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recent advances in Takayasu arteritis (2014)
  • Author(s): Terao C, Yoshifuji H, Mimori T
  • Journal Title: International Journal of Rheumatic Diseases Volume: 17(3) Issue: 3 Pages: 238-47
  • DOI: 10.1111/1756-185x.12309
  • Peer Reviewed
• [Journal Article] History of Takayasu arteritis and Dr. Mikito Takayasu (2014)
  • Author(s): Terao C
  • Journal Title: International Journal of Rheumatic Diseases Volume: 17(8) Issue: 8 Pages: 931-5
  • DOI: 10.1111/1756-185x.12576
  • NAID: 120005657900
  • Peer Reviewed
• [Journal Article] Susceptibility HLA alleles and amino acids to Takayasu Arteritis (2014)
  • Author(s): Terao C, Yoshifuji H, Mimori T, Matsuda F.
  • Journal Title: Nihon Rinsho Meneki Gakkai Kaishi Volume: 37(3) Pages: 166-70
  • NAID: 130004875929
  • Peer Reviewed
• [Journal Article] Two Susceptibility Loci to Takayasu Arteritis Reveal a Synergistic Role of the IL12B and HLA-B Regions in a Japanese Population (2013)
  • Author(s): Terao C, Yoshifuji H, Kimura A, Matsumura T, Ohmura K, Takahashi M, Shimizu M, Kawaguchi T, Chen Z, Naruse TK, Sato-Otsubo A, Ebana Y, Maejima Y, Kinoshita H, Murakami K, Kawabata D, Wada Y, Narita I,
  • Journal Title: American Journal of Human Genetics Volume: 93 Issue: 2 Pages: 289-297
  • DOI: 10.1016/j.ajhg.2013.05.024
  • Peer Reviewed
• [Journal Article] Association of Takayasu arteritis with HLA-B*67:01 and two amino acids in HLA-B protein. (2013)
  • Author(s): Terao C, Yoshifuji H, Ohmura K, Murakami K, Kawabata D, Yurugi K, Tazaki J, Kinoshita H, Kimura A, Akizuki M, Kawaguchi Y, Yamanaka H, Miura Y, Maekawa T, Saji H, Mimori T
  • Journal Title: Rheumatology Volume: 52(10) Issue: 10 Pages: 1769-1774
  • DOI: 10.1093/rheumatology/ket241
  • Peer Reviewed
• [Presentation] 潰瘍性大腸炎は高安動脈炎の主要な合併症であり、合併にはHLA-B*52:01が特に重要であって両疾患は遺伝因子を共有している (2014)
  • Author(s): 寺尾 知可史, 松村 貴由, 吉藤 元, 桐野 洋平, 前嶋 康浩, 中岡 良和, 高橋 めい子, 網谷 英介, 田村 夏子, 中島 俊樹, 折口 智樹, 大村 浩一郎, 桑名 正隆, 小室 一成, 上田 敦久, 磯部 光章, 三森 経世, 松田 文彦
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: タワーホール船堀
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] Takayasu Arteritis and Ulcerative Colitis -High Concurrence Ratio and Genetic Overlap (2014)
  • Author(s): Chikashi Terao, Takayoshi Matsumura, Hajime Yoshifuji, Yohei Kirino et al.
  • Organizer: 米国リウマチ学会
  • Place of Presentation: ボストン
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] 高安動脈症炎の新規疾患関連遺伝子IL12Bと臨床病態との関連 (2014)
  • Author(s): 中島 俊樹、吉藤 元、寺尾 知可史、井村 嘉孝、中嶋 蘭、湯川 尚一郎、大村 浩一郎、藤井 隆夫、三森 経世
  • Organizer: 第111回日本内科学会講演会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] IL12Bは高安動脈炎の新規疾患感受性遺伝子でありHLA-B*52:01と相互作用を示す (2013)
  • Author(s): 寺尾知可史, 吉藤元, 木村彰方,松村 貴由,大村 浩一郎,成瀬 妙子,佐藤 愛子,前島 康浩,和田 庸子,成田 一衛,川口 鎮司,山中 寿,前川 平,小川 誠司,小室 一成,永井良三, 田原 康玄,磯部 光章,三森 経世,松田 文彦
  • Organizer: 第４１回日本臨床免疫学会
  • Place of Presentation: 下関
• [Presentation] 高安動脈炎感受性と相関する3つの新規HLA-Bアミノ酸多型 (2013)
  • Author(s): 寺尾 知可史、吉藤 元、村上 孝作、 川端 大介、大村 浩一郎、秋月 正史、 川口 鎮司、山中 寿、三森 経世
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Association between HLA-B’s amino acid variation and disease-susceptibility to Takayasu arteritis (2013)
  • Author(s): Hajime Yoshifuji, Chikashi Terao, Kosaku Murakami, Daisuke Kawabata, Koichiro Ohmura, Takao Fujii, Yasushi Kawaguchi, Hisashi Yamanaka, and Tsuneyo Mimori
  • Organizer: 米国リウマチ学会
  • Place of Presentation: サンディエゴ
• [Book] 分子リウマチ治療 (2015)
  • Author(s): 寺尾 知可史
  • Publisher: 先端医学社
• [Book] 感染・炎症・免疫vol44.1 (2014)
  • Author(s): 寺尾 知可史
  • Total Pages: 88
  • Publisher: 鳥井薬品株式会社