Investigation of the onset and progression mechanisms of primary open-angle glaucoma -Involvement of genetic variants associated with primary open-angle glaucoma in phenotypic features-

• Project/Area Number: 18K09400
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: University of Yamanashi
• Principal Investigator: Mabuchi Fumihiko 山梨大学, 大学院総合研究部, 医学研究員 (20322125)
• Co-Investigator(Kenkyū-buntansha): 柏木 賢治 山梨大学, 大学院総合研究部, 教授 (30194723) ; 櫻田 庸一 山梨大学, 大学院総合研究部, 准教授 (90456476) ; 米山 征吾 山梨大学, 大学院総合研究部, 助教 (90751652)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); 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); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 原発開放隅角緑内障 / 遺伝子多型 / 眼圧 / genetic risk score / 緑内障家族歴 / 緑内障診断時年齢 / POAG / IOP / 家族歴 / 診断時年齢 / polygenic risk score / 感受性遺伝子多型

Outline of Final Research Achievements

Genetic variants predisposing to primary open-angle glaucoma (POAG) can be classified into 2 types: 1 type involves genetic variants associated with IOP elevation (IOP-related genetic variants) and the other type involves genetic variants associated with vulnerability of the optic nerve, independent of IOP (non-IOP-related genetic variants).
In the present study, the associations between the IOP-/non-IOP-related genetic variants and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. It was found that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma).

Academic Significance and Societal Importance of the Research Achievements

本研究により、POAGの発症進行メカニズムが遺伝学的により明らかとなった。これら遺伝情報の積み重ねから、将来的には緑内障になりやすい症例の発症前診断、緑内障進行リスクを遺伝学的に評価することが可能となり、早期発見治療が重要と考えられている緑内障診療の一助となるだけでなく、進行リスクに合わせた目標眼圧設定、治療法選択が可能となるかもしれない。また、個々の症例の臨床像(表現型)と遺伝背景に合わせて、最適かつ有効な治療の選択といった、いわゆるオーダーメイド医療を行える可能性もあり、より質の高い医療を提供できると共に医療経済的にも有益であると考えられ、今後の緑内障治療発展の足掛かりとなった。

Research Products

• [Int'l Joint Research] New York University School of Medicine(米国)
• [Int'l Joint Research] New York University School of Medicine(米国)
• [Int'l Joint Research] Singapore National Eye Centre/Duke-NUS Medical School/National University of Singapore(シンガポール)
• [Int'l Joint Research] Harvard Medical School/Duke University/Case Western Reserve University(米国)
• [Int'l Joint Research] Flinders University/University of Melbourne/University of Tasmania(オーストラリア)
• [Int'l Joint Research] University of Ibadan(ナイジェリア)
• [Int'l Joint Research] University of Ghana(ガーナ)
• [Int'l Joint Research]
• [Journal Article] Genetic variants associated with the onset and progression of primary open-angle glaucoma (2020)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Iijima H, Yamagata Z, Takamoto M, Aihara M, Iwata T, Hashimoto K, Sato K, Shiga Y, Nishiguchi KM, Nakazawa T, Akiyama M, Kawase K, Ozaki M, Araie M, Japan Glaucoma Society Omics Group (JGS-OG)
  • Journal Title: American Journal of Ophthalmology Volume: 212 Pages: 135-140
  • DOI: 10.1016/j.ajo.2020.03.014
  • Peer Reviewed
• [Journal Article] Genetics of primary open-angle glaucoma and its endophenotypes (2020)
  • Author(s): Sakurada Y, Mabuchi F, Kashiwagi K.
  • Journal Title: Prog Brain Res Volume: 256 Pages: 31-47
  • DOI: 10.1016/bs.pbr.2020.06.001
  • Peer Reviewed
• [Journal Article] Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy (2020)
  • Author(s): Yoneyama S, Sakurada Y, Kikushima W, Sugiyama A, Matsubara M, Fukuda Y, Tanabe N, Parikh R, Mabuchi F, Kashiwagi K, Iijima H.
  • Journal Title: Sci Rep Volume: 28 Issue: 1 Pages: 7188-7188
  • DOI: 10.1038/s41598-020-64301-z
  • Peer Reviewed / Open Access
• [Journal Article] Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration (2020)
  • Author(s): Shijo T, Sakurada Y, Yoneyama S, Kikushima W, Sugiyama A, Matsubara M, Fukuda Y, Mabuchi F, Kashiwagi K.
  • Journal Title: Pharmaceuticals (Basel) Volume: 20 Issue: 9 Pages: 257-257
  • DOI: 10.3390/ph13090257
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma (2018)
  • Author(s): Shiga Yukihiro、Kashiwagi Kenji、Nakazawa Toru、Kubo Michiaki、Japan Glaucoma Society Omics Group (JGS-OG)、NEIGHBORHOOD Consortium
  • Journal Title: Human Molecular Genetics Volume: 27 Issue: 8 Pages: 1486-1496
  • DOI: 10.1093/hmg/ddy053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic variants associated with progression of visual field defect in primary open-angle glaucoma (2019)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Iijima H, Yamagata Z, Takamoto M, Aihara M, Iwata T, Kawase K, Hashimoto K, Sato K, Shiga Y, Nishiguchi KM, Nakazawa T, Ozaki M, Araie M, for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Organizer: World Glaucoma Congress (WGC)
  • Int'l Joint Research
• [Presentation] Prediction of glaucomatous visual field progression by genetic variants associated with primary open-angle glaucoma (2019)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Iijima H, Yamagata Z, Takamoto M, Aihara M, Iwata T, Hashimoto K, Sato K, Shiga Y, Nishiguchi KM, Nakazawa T, Akiyama M, Kawase K, Ozaki M, Araie M, for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Organizer: Association for Research in Vision and Ophthalmology (ARVO)
  • Int'l Joint Research
• [Presentation] Method for predicting disease onset risk by genetic variants associated with primary open-angle glaucoma (2019)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Yamagata Z, Iijima H, for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Organizer: American Society of Human Genetics (ASHG)
  • Int'l Joint Research
• [Presentation] Association between additive effects of genetic variants associated with primary open-angle glaucoma and family history of glaucoma (2018)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Yamagata Z, Iijima H, for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Organizer: European Glaucoma Society (EGS)
  • Int'l Joint Research
• [Presentation] Association between additive effects of genetic variants associated with primary open-angle glaucoma and age at diagnosis of glaucoma (2018)
  • Author(s): Mabuchi F, Mabuchi N, Sakurada Y, Yoneyama S, Kashiwagi K, Iijima H, Yamagata Z, Takamoto M, Aihara M, Iwata T, Kawase K, Shiga Y, Nishiguchi KM, Nakazawa T, Ozaki M, Araie M, for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Organizer: American Society of Human Genetics (ASHG)
  • Int'l Joint Research
• [Presentation] 多型解析によるPOAG発症進行メカニズム解明とリスク予測 ―スクリーニングチップ臨床応用にむけて― (2018)
  • Author(s): 間渕文彦
  • Organizer: 日本緑内障学会
  • Invited
• [Book] 眼科 (2018)
  • Author(s): 間渕文彦
  • Total Pages: 7
  • Publisher: 金原出版