Pathogenesis of age-related macular degeneration and pachychoroid neovasculopathy

• Project/Area Number: 20H03841
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Kyoto University
• Principal Investigator: Miyake Masahiro 京都大学, 医学研究科, 特定講師 (90812793)
• Co-Investigator(Kenkyū-buntansha): 辻川 明孝 京都大学, 医学研究科, 教授 (40402846) ; 杉山 治 近畿大学, 情報学部, 准教授 (40586038) ; 長崎 正朗 京都大学, スーパーグローバルコース医学生命系ユニット, 特定教授 (90396862) ; 山田 亮 京都大学, 医学研究科, 教授 (50301106)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 中心性漿液性脈絡網膜症 / パキコロイド新生血管 / 加齢黄斑変性 / ゲノムワイド関連解析 / パキコロイド / ゲノムワイド生存解析 / 機械学習 / 人工知能

Outline of Research at the Start

加齢黄斑変性（AMD）は先進国の失明原因の上位を占める疾患であるが、欧米人とアジア人で表現型に差がある。かつては人種差と考えられてきたが、研究代表者は、パキコロイド新生血管（PNV）という類似病態の混在が影響を与えている可能性を指摘した。本研究の目的はAMDとPNVの病態解明である。このため、研究代表者が機械学習の応用により策定したAMD/PNV診断基準をベースに、研究代表者の専門であるAMD/PNVの臨床研究と、同じく研究代表者の得意とするゲノム疫学的アプローチ、臨床ゲノム的アプローチ及び深層学習の技術を組み合わせる。

Outline of Final Research Achievements

This study analyzed the genomics and omics of central serous chorioretinopathy (CSC) and pachychoroid neovasculopathy (PNV). (1) Survival analysis was performed on CSC patients for the time to onset of PNV, revealing a significant association with the susceptibility gene for age-related macular degeneration, ARMS2, at the genome-wide level. Pathway analysis showed enrichment of ion transport-related pathways. (2) An international collaborative study exploring the susceptibility genes for CSC found a significant association with one variant related to cortisol levels in the blood. (3) Additionally, the natural progression of PNV, distribution of choroidal thickness, and the relationship between choroidal parameters and the genome were also discussed in the paper.

Academic Significance and Societal Importance of the Research Achievements

加齢黄斑変性は本邦の失明原因の上位に位置する疾患である。パキコロイド新生血管は、日本人でこれまで加齢黄斑変性と診断されてきたもののうち半数程度を占める病態であり、その病態解明は極めて重要である。また、パキコロイド新生血管は中心性漿液性脈絡網膜症を母体として発症することから、中心性漿液性脈絡網膜症の病態を解明することも同様に重要である。本研究によってこれらの病態の一端を解明することができ、本邦における加齢黄斑変性治療戦略に大きく貢献することが期待される。

Research Products

• [Int'l Joint Research] Radbout University(オランダ)
• [Int'l Joint Research] Institute for Molecular Medicine Finland/University of Helsinki(フィンランド)
• [Int'l Joint Research] Chinese University of Hong Kong/Shantou University(中国)
• [Int'l Joint Research] DUKE-NUS Medical School(シンガポール)
• [Journal Article] Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy (2023)
  • Author(s): Akiyama Masato、Miyake Masahiro、Momozawa Yukihide、Honda Shigeru、et al.
  • Journal Title: Ophthalmology Volume: 130 Issue: 4 Pages: 361-372
  • DOI: 10.1016/j.ophtha.2022.10.034
  • Peer Reviewed
• [Journal Article] Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy (2022)
  • Author(s): Mori Yuki、Miyake Masahiro、Hosoda Yoshikatsu、Miki Akiko、Takahashi Ayako、Muraoka Yuki、Miyata Manabu、Sato Takehiro、Tamura Hiroshi、Ooto Sotaro、Yamada Ryo、Yamashiro Kenji、Nakamura Makoto、Tajima Atsushi、Nagasaki Masao、Honda Shigeru、Tsujikawa Akitaka
  • Journal Title: Ophthalmology Volume: 129 Issue: 9 Pages: 1034-1042
  • DOI: 10.1016/j.ophtha.2022.04.018
  • Peer Reviewed
• [Journal Article] Natural Course of Pachychoroid Pigment Epitheliopathy (2022)
  • Author(s): Yagi Mariko、Miyake Masahiro、Mori Yuki、Hosoda Yoshikatsu、Takahashi Ayako、Muraoka Yuki、Ueda-Arakawa Naoko、Miyata Manabu、Yamashiro Kenji、Tamura Hiroshi、Ooto Sotaro、Tsujikawa Akitaka
  • Journal Title: Ophthalmology Science Volume: 2 Issue: 4 Pages: 100201-100201
  • DOI: 10.1016/j.xops.2022.100201
  • Peer Reviewed / Open Access
• [Journal Article] Association between central serous chorioretinopathy susceptibility genes and choroidal parameters (2022)
  • Author(s): Kazuya Morino , Masahiro Miyake , Takuro Kamei , Takahisa Kawaguchi , Yuki Mori , Yoshikatsu Hosoda , Akihito Uji , Kenji Yamashiro , Fumihiko Matsuda , Akitaka Tsujikawa
  • Journal Title: Japanese Journal of Ophthalmology Volume: 66 Issue: 6 Pages: 504-510
  • DOI: 10.1007/s10384-022-00945-w
• [Journal Article] Distribution of Choroidal Thickness and Choroidal Vessel Dilation in Healthy Japanese Individuals (2021)
  • Author(s): Mori Yuki、Miyake Masahiro、Hosoda Yoshikatsu、Uji Akihito、Nakano Eri、Takahashi Ayako、Muraoka Yuki、Miyata Manabu、Tamura Hiroshi、Ooto Sotaro、Tabara Yasuharu、Yamashiro Kenji、Matsuda Fumihiko、Tsujikawa Akitaka、Nakayama Takeo、Sekine Akihiro、Kosugi Shinji、Tabara Yasuharu、Matsuda Fumihiko
  • Journal Title: Ophthalmology Science Volume: 1 Issue: 2 Pages: 100033-100033
  • DOI: 10.1016/j.xops.2021.100033
  • Peer Reviewed / Open Access
• [Journal Article] Incidence of central serous chorioretinopathy (2011?2018): a nationwide population-based cohort study of Japan (2021)
  • Author(s): Kido Ai、Miyake Masahiro、Tamura Hiroshi、Hiragi Shusuke、Kimura Takeshi、Ohtera Shosuke、Takahashi Ayako、Ooto Sotaro、Kawakami Koji、Kuroda Tomohiro、Tsujikawa Akitaka
  • Journal Title: British Journal of Ophthalmology Volume: NA Issue: 12 Pages: 2021-319403
  • DOI: 10.1136/bjophthalmol-2021-319403
  • Peer Reviewed / Open Access
• [Presentation] ゲノムから迫るパキコロイドと近視 (2021)
  • Author(s): 三宅正裕
  • Organizer: 日本網膜硝子体学会
  • Invited
• [Presentation] 中心性漿液性脈絡網膜症の発症に関するゲノムワイドメタ関連解析 (2021)
  • Author(s): 森雄貴、三宅正裕、ほか
  • Organizer: 日本臨床眼科学会
• [Presentation] Exploration of pachychoroid disease (2021)
  • Author(s): Masahiro Miyake
  • Organizer: 日本眼循環学会
  • Invited
• [Presentation] Genetic and Epidemiological Background of Choroid and Pachychoroid Diseases (2021)
  • Author(s): Masahiro Miyake
  • Organizer: EURETINA
  • Invited
• [Presentation] 中心性漿液性脈絡網膜症僚眼に見られるパキコロイド色素上皮症の自然経過 (2021)
  • Author(s): 八木真利子、三宅正裕、ほか
  • Organizer: 日本眼科学会
• [Presentation] Incidence of Central Serous Chorioretinopathy in Japan: A Nationwide Population-Based Cohort Study (2021)
  • Author(s): Akitaka Tsujikawa, Ai Kido, Masahiro Miyake, Hiroshi Tamura
  • Organizer: Macula Society
  • Int'l Joint Research
• [Presentation] Genome-wide Survival Analysis IdentifiesGenes associated with Occurrence of Chroidal Neovascularizationin Central Serous Chorioretinopathy (2020)
  • Author(s): Yuki Mori1), Masahiro Miyake1), Yoshikatsu Hosoda1),Ayako Takahashi1), Yuki Muraoka1), Akihito Uji1),Manabu Miyata1), Akio Oishi1), Kenji Yamashiro2),Hiroshi Tamura1), Sotaro Ooto1), Akitaka Tsujikawa1)
  • Organizer: EURETINA2020
  • Int'l Joint Research
• [Presentation] Genes Associated withOccurrence of Choroidal Neovasculizationin Central Serous Chorioretinopathy (2020)
  • Author(s): Yuki Mori1), Masahiro Miyake1), Yoshikatsu Hosoda1),Ayako Takahashi1), Yuki Muraoka1), Akihito Uji1),Manabu Miyata1), Akio Oishi1), Kenji Yamashiro2),Hiroshi Tamura1), Sotaro Ooto1), Akitaka Tsujikawa1)
  • Organizer: 第124回日本眼科学会総会