Exploring novel genetic factors associated with intravenous immunoglobulin therapy-unresponsiveness in Kawasaki disease patients

• Project/Area Number: 18K15666
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Shinshu University
• Principal Investigator: Amano Yuji 信州大学, 学術研究院医学系, 助教 (50624681)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 川崎病 / IVIG療法抵抗性 / 遺伝子解析 / pooled genome sequencing / インターロイキン4受容体

Outline of Final Research Achievements

We performed exome sequencing followed by deep sequencing using pooled genomic DNA derived from 30 of IVIG-unresponsive Kawasaki disease (KD) patients. As a result, we selected 8 variants as candidates. Individual genotyping showed that a low frequency missense variant located in SMURF2 locus is concentrated in IVIG-unresponsive KD patients(p=4.5e-5). We examined clinical characteristics of KD patients harboring this variant, and found that this variant is a protective factor for the development of coronary artery lesions in IVIG-unresponsive KD patients(p=0.0365).

Academic Significance and Societal Importance of the Research Achievements

SMURF2は、IVIG抗炎症作用および川崎病急性期炎症と密接に関与するTGF-betaシグナルのネガティブレギュレーターとして知られている。アミノ酸置換を伴う本バリアントは、SMURF2の分子機能に影響を及ぼす可能性が高い。その詳細解析はIVIGの抗炎症効果の分子機序解明につながる可能性を秘めている。更に本バリアントは日本人の約0.6％がヘテロに保有する低頻度バリアントであるにもかかわらず、約13％のIVIG不応性川崎病患者がヘテロに保有していた(OR(95%CI)=25.9(8.3-80.6))。更なる検証を行うことにより、IVIG不応性予測指標へと繋がる事が期待される。

Research Products

• [Journal Article] A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease. (2019)
  • Author(s): Yuji Amano, Yohei Akazawa, Jun Yasud, Kazuhisa Yoshino, Katsuhiko Kojima, Norimoto Kobayashi, Satoshi Matsuzaki, Masao Nagasaki, Yosuke Kawai, Naoko Minegishi, Noriko Ishida, Noriko Motoki, Akira Hachiya, Yozo Nakazawa, Masayuki Yamamoto, Kenichi Koike, Toshikazu Takeshita
  • Journal Title: Pediatr Rheumatol Volume: 17 Issue: 1 Pages: 1-11
  • DOI: 10.1186/s12969-019-0337-2
  • NAID: 120007113478
  • Peer Reviewed / Open Access