Genome-Wide Association Study of Hunner-type Interstitial Cystitis

• Project/Area Number: 19K18552
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: The University of Tokyo
• Principal Investigator: AKIYAMA Yoshiyuki 東京大学, 医学部附属病院, 講師 (20529135)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 全ゲノム関連解析 / ハンナ型間質性膀胱炎 / HLA imputation / GWAS / Genotype imputation / 間質性膀胱炎（ハンナ型） / 遺伝子多型

Outline of Research at the Start

ハンナ型間質性膀胱炎は病因が不明で確立した治療を欠く指定難病である。これまでに、病因として様々な説が挙げられてきたが未だ決定的なものはない。加えて、その疫学的要因（性差、感染、加齢）や発症に関する遺伝学的背景は不明である。そこで本研究では、ハンナ型間質性膀胱炎患者の全ゲノム関連解析を行い、発症に関わる疾患感受性遺伝子の探索を行う。さらに、得られた感受性遺伝子と多様な生物学的データベースや臨床病理学的データとの照合を行い、治療標的となる遺伝子を絞り込む。これらによって、ハンナ型間質性膀胱炎の発症に関与する遺伝的要因を明らかにし、病態生理の解明や新たな治療標的の発見、治療薬の開発を目的とする。

Outline of Final Research Achievements

To examine the roles of human leukocyte antigen (HLA), which has been known to be associated with the risk of various autoimmune diseases, for Hunner-type interstitial cystitis (HIC) pathogenesis in Japanese, we fine-mapped HLA in 1,044 individuals (148 patients with HIC and 896 controls) We identified that one of the class Ⅱ HLA alleles of HLA-DQB1 was significantly associated with HIC risk. The conditional analysis demonstrated that no other HLA alleles remained significant after conditioning on the HLA-DQB1, suggesting that HLA-DQB1 could explain most of the MHC risk associated with HIC risk. The HLA amino acid residue-based analysis suggested that the amino acid position 75 of HLA-DQB1 plays a key role in the susceptibility to HIC (presence of valine being a risk, P = 1.4 × 10-6)

Academic Significance and Societal Importance of the Research Achievements

本研究では、世界中で精力的に病態解明研究が行われているにも関わらず未だ病因不明の難病であるハンナ型間質性膀胱炎の発症に遺伝的要因が関与することを世界で初めて全ゲノム関連解析を施行して明らかにした。過去の研究から、HICは免疫学的異常を伴うことが示唆されていたが、本研究で特定された疾患感受性遺伝子領域は古典的ＭＨＣクラスⅡ領域のバリアントであり、非常に合理的な結果である。本研究結果からハンナ型間質性膀胱炎が免疫関連疾患であることはほぼ間違いなく、今後の治療法開発や病態解明の進歩に大きく寄与する点で学術的・社会的意義は大きい。現在、Nature関連雑誌への投稿を準備中である。

Research Products

• [Int'l Joint Research] University of Iowa(米国)
• [Journal Article] Relationship between the frequency of electrocautery of Hunner lesions and changes in bladder capacity in patients with Hunner type interstitial cystitis (2021)
  • Author(s): Akiyama Y, Zaitsu M, Watanabe D, Yoshimura I, Niimi A, Nomiya A, Yamada Y, Sato Y, Nakamura M, Kawai T, Yamada D, Suzuki M, Kume H, Homma Y
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 105-105
  • DOI: 10.1038/s41598-020-80589-3
  • Peer Reviewed / Open Access
• [Journal Article] Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain and voiding dysfunction: a novel animal model for Hunner type interstitial cystitis (2021)
  • Author(s): Akiyama Y, Yao JR, Kreder KJ, O'Donnell MA, Lutgendorf SK, Lyu D, Maeda D, Kume H, Homma Y, and Luo Y.
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 320 Issue: 2 Pages: F174-F182
  • DOI: 10.1152/ajprenal.00290.2020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical characterization of interstitial cystitis/bladder pain syndrome in women based on the presence or absence of Hunner lesions and glomerulations (2020)
  • Author(s): Watanabe D, Akiyama Y, Niimi A, Nomiya A, Yamada Y, Sato Y, Nakamura M, Kawai T, Yamada D, Suzuki M, Igawa Y, Kume H, Homma Y
  • Journal Title: Low Urin Tract Symptoms Volume: 13 Issue: 1 Pages: 139-143
  • DOI: 10.1111/luts.12344
  • Peer Reviewed
• [Journal Article] Interstitial cystitis/bladder pain syndrome: The Evolving Landscape, Animal Models, and Future Perspectives. (2020)
  • Author(s): Akiyama Y, Luo Yi, Hanno P, Maeda D, Homma Y.
  • Journal Title: International journal of Urology Volume: Epub Ahead of Print Issue: 6 Pages: 0-0
  • DOI: 10.1111/iju.14229
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical guidelines for interstitial cystitis/bladder pain syndrome. (2020)
  • Author(s): Homma Y, Akiyama Y, Tome H, Furuta A, Ueda T, Maeda D, Lin AT, Kuo HC, Lee MH, Oh SJ, Kim JC, Lee KS
  • Journal Title: International journal of Urology Volume: Epub Ahead of Print Issue: 7 Pages: 0-0
  • DOI: 10.1111/iju.14234
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Update on the pathophysiology of interstitial cystitis/bladder pain syndrome. (2020)
  • Author(s): Akiyama Y
  • Journal Title: Current Bladder Dysfunction Reports Volume: 15 Issue: 1 Pages: 1-8
  • DOI: 10.1007/s11884-019-00569-w
• [Presentation] 高精度 HLA タイピング技術（HLA imputation）によるハンナ型間質性膀胱炎の疾患ゲノム関連解析. (2021)
  • Author(s): 秋山佳之
  • Organizer: 第109回日本泌尿器科学会総会
• [Presentation] Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain and voiding dysfunction: a novel animal model for Hunner type interstitial cystitis (2020)
  • Author(s): Akiyama Y, Lutgendorf S, Kreder K, O’Donnell M, Homma Y, Kume H, Luo Y
  • Organizer: The 50th International Continence Society (ICS) annual meeting. 2020 Nov 22nd. (online meeting)
  • Int'l Joint Research
• [Presentation] Comparative transcriptome analysis of interstitial cystitis/bladder pain syndrome with Hunner lesions and Bacillus Calmette Guerin related cystitis by next generation RNA sequencing: Discovery of disease specific genes and associated biological pathways (2020)
  • Author(s): Yoshiyuki Akiyama, Daichi Maeda, Hiroto Katoh, Haruki Kume, Yukio Homma
  • Organizer: 35th European Association of Urology annual meeting. 2020 July 18th. (Virtual)
  • Int'l Joint Research
• [Presentation] Are glomerulations still characteristic marker for interstitial cystitis/bladder pain syndrome?: Biological evidences from global gene expression and comprehensive immunohistochemical quantification analyses (2020)
  • Author(s): Yoshiyuki Akiyama, Daichi Maeda, Hiroto Katoh, Haruki Kume, Yukio Homma
  • Organizer: 35th European Association of Urology annual meeting. 2020 July 18th. (Virtual)
  • Int'l Joint Research