Exploration of the genes which are responsible for the pathogenesis of Takayasu arteritis

• Project/Area Number: 26670399
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISOBE MITSUAKI 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (80176263)
• Co-Investigator(Kenkyū-buntansha): 前嶋 康浩 東京医科歯科大学, 医学部附属病院, 講師 (40401393) ; 江花 有亮 東京医科歯科大学, 学内共同利用施設等, 講師 (60517043)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 高安動脈炎 / 一塩基多型 / インフラマソーム / 遺伝子多型 / 転写因子 / サイトカイン

Outline of Final Research Achievements

Takayasu arteritis (TA) is an autoimmune systemic arteritis of unknown etiology. We have identified that single nucleotide polymorphisms (SNPs) of MLX gene, which encodes MLX transcription factor, was significantly associated with clinical manifestations of TA by genome-wide association study. The SNPs of MLX (rs665268) is a missense mutation of MLX that alters the Gln139 to Arg(Q139R). As Gln139 is located on the DNA binding site of MLX, we hypothesized that the mutation of Q139R on MLX, which alters the electric charge of the amino acid may enhance the formation of the MLX-DNA complex. Then, based on our experimental results, we concluded that MLX-Q139R mutation plays a crucial role in the pathogenesis of TA through facilitating inflammasome formation, which in turn promoting proliferation and adhesion ability of aorta-resident cells, a pathological manifestation seen in the aortas of TA.

Research Products

• [Journal Article] Profiles of serum cytokine levels in Takayasu arteritis patients: Potential utility as biomarkers for monitoring disease activity. (2017)
  • Author(s): Tamura N, Maejima Y, Tezuka D, Takamura C, Yoshikawa S, Ashikaga T, Hirao K, Isobe M.
  • Journal Title: J Cardiol Volume: 印刷中 Issue: 3 Pages: 278-285
  • DOI: 10.1016/j.jjcc.2016.10.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. (2017)
  • Author(s): Ohigashi H, Tamura N, Ebana Y, Harigai M, Maejima Y, Ashikaga T, Isobe M.
  • Journal Title: J Cardiol Volume: 69 Issue: 5 Pages: 774-778
  • DOI: 10.1016/j.jjcc.2016.07.009
  • Peer Reviewed
• [Journal Article] Endoscopic features and genetic background of inflammatory bowel disease complicated with Takayasu arteritis. (2017)
  • Author(s): Akiyama S, Fujii T, Matsuoka K, Yusuke E, Negi M, Takenaka K, Nagahori M, Ohtsuka K, Isobe M, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 5 Pages: 1011-1017
  • DOI: 10.1111/jgh.13640
  • Peer Reviewed
• [Journal Article] Obstetrical management of patients with extra-anatomic vascular bypass grafts due to Takayasu arteritis. (2016)
  • Author(s): Miyasaka N, Egawa M, Isobe M, Inoue Y, Kubota T
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 12 Pages: 1864-1869
  • DOI: 10.1111/jog.13139
  • Peer Reviewed
• [Journal Article] Vessel Wall Inflammation of Takayasu Arteritis Detected by Contrast-Enhanced Magnetic Resonance Imaging: Association with Disease Distribution and Activity. (2015)
  • Author(s): Kato Y, Terashima M, Ohigashi H, Tezuka D, Ashikaga T, Hirao K, Isobe M.
  • Journal Title: PLoS One Volume: 10(12) Issue: 12 Pages: e0145855-e0145855
  • DOI: 10.1371/journal.pone.0145855
  • Peer Reviewed / Open Access
• [Journal Article] Takayasu arteritis and ulcerative colitis -high concurrence ratio and genetic overlap. (2015)
  • Author(s): Terao C, Matsumura T, Yoshifuji H, Kirino Y, Maejima Y, Kochi Y, Ogimoto A, Yamamoto M, Takahashi H, Nakayamada S, Saito K, Wada Y, Narita I, Kawaguchi Y, Yamanaka H, Ohmura K, Atsumi T, Tanemoto K, Miyata T, Kuwana M, Komuro I, Tabara Y, Ueda A, Isobe M, Mimori T, Matsuda F.
  • Journal Title: Arthritis Rheumatol. Volume: - Issue: 8 Pages: 2226-2232
  • DOI: 10.1002/art.39157
  • Peer Reviewed
• [Journal Article] A novel susceptibility locus for Takayasu arteritis in the IL12B region can be a genetic marker of disease severity. (2015)
  • Author(s): Matsumura T, Amiya E, Tamura N, Maejima Y, Komuro I, Isobe M.
  • Journal Title: Heart Vessels. Volume: 0 Pages: 0-0
  • Peer Reviewed
• [Presentation] The Single nucleotide polymorphism of MLX gene plays a critical role in the pathogenesis of Takayasu Arteritis by enhancing NLRP3-inflammasome formation (2017)
  • Author(s): 田村夏子、前嶋康浩、磯部光章
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
• [Presentation] Current diagnosis and treatment of Takayasu arteritis in Japan (2017)
  • Author(s): Mitsuaki Isobe
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Invited
• [Presentation] 日本が誇る循環器研究 - 高安動脈炎 (2016)
  • Author(s): 磯部光章
  • Organizer: 第80回日本循環器学会学術集会（会長特別企画）
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] Single nucleotide polymorphism of MLX gene is associated with the pathogenesis of Takayasu Arteritis by enhancing inflammasome formation (2016)
  • Author(s): 田村夏子
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] The Gln139Arg single nucleotide polymorphism of Takayasu arteritis by promoting NLRP3-inflammasome formation. (2016)
  • Author(s): 田村夏子、前嶋康浩、磯部光章
  • Organizer: 第33回国際心臓研究学会日本部会 YIA審査講演
  • Place of Presentation: 東京コンベンションホール（東京都中央区）
• [Presentation] Single nucleotide polymorphism of MLX gene causes TXNIP accumulation and inflammasome formation, thereby promoting the development of Takayasu arteritis (2015)
  • Author(s): 田村夏子
  • Organizer: 米国心臓協会学術集会2015
  • Place of Presentation: 米国、オーランド
  • Year and Date: 2015-11-08
  • Int'l Joint Research
• [Presentation] 温故知新：高安病の今、昔 (2015)
  • Author(s): 磯部光章
  • Organizer: 第56回日本脈管学会総会（会長講演）
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-10-29
  • Invited
• [Presentation] 高安動脈炎の感受性遺伝子MLXの一塩基 多型による発症・病状進展への関与についての検討 (2015)
  • Author(s): 前嶋康浩
  • Organizer: 第56回日本脈管学会総会（シンポジウム）
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-10-29
  • Invited
• [Presentation] 高安動脈炎の病勢診断に有用な血中サイトカインについての検討 (2015)
  • Author(s): 田村夏子
  • Organizer: 第56回日本脈管学会総会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-10-29
• [Presentation] Single Nucleotide Polymorphism of MLX Gene Plays a Crucial Role in the Pathogenesis of Takayasu Arteritis Through Facilitating Inflammasome Formation of the Aorta (2015)
  • Author(s): 前嶋康浩
  • Organizer: BCVS-AHA年次集会2015
  • Place of Presentation: 米国、ニューオリンズ
  • Year and Date: 2015-07-13
  • Int'l Joint Research
• [Presentation] Mutation of MLX gene plays an important role in the pathogenesis of Takayasu Arteritis by promoting inflammasome formation. (2014)
  • Author(s): Maejima Y, Tamura N, Isobe M.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago, USA.
  • Year and Date: 2014-11-18
• [Presentation] 血中サイトカイン濃度測定による高安動脈炎の病勢診断 (2014)
  • Author(s): 田村夏子、前嶋康浩、高村千智、吉川俊治、足利貴志、平生見三、磯部光章
  • Organizer: 第62回日本心臓病学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2014-09-26