原発開放隅角緑内障発症進行メカニズムの解明 －感受性遺伝子多型の表現型への関与－

• 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: 間渕 文彦 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, 講師 (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: Granted (Fiscal Year 2019)
• 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 / 家族歴 / 診断時年齢 / POAG / IOP / polygenic risk score / 感受性遺伝子多型

Outline of Annual Research Achievements

原発開放隅角緑内障(POAG)感受性遺伝子多型は、眼圧(IOP)上昇に関与するIOP-related遺伝子多型と、眼圧とは別に視神経の脆弱性に関与するnon-IOP-related遺伝子多型の2つに分類される。我々は、眼圧がIOP-related遺伝子多型の相加効果により上昇すること、IOP-related遺伝子多型、non-IOP-related遺伝子多型をどのくらい持つかによって、正常眼圧緑内障、狭義POAG、高眼圧症いずれかの表現型を呈する可能性を報告した。本研究では、POAG発症にはnon-IOP-related遺伝子多型、進行にはIOP-related遺伝子多型が重要な役割を果たしていることを検証する。
今年度は、IOP-related遺伝子多型であるrs945686 (近傍の遺伝子: LMX1B)、rs10505100 (ANGPT1)、rs61394862 (ANKH)、rs7924522 (ETS1)、non-IOP-related遺伝子多型と思われるrs61861119 (MYOF)の遺伝子型をTaqMan genotyping assay法にて同定。POAG感受性遺伝子多型の相加効果を評価するため、複数のIOP-related遺伝子多型のrisk allele数の合計をgenetic risk score (GRS)として各症例毎に算出。同様にnon-IOP-related遺伝子多型についてもGRSを算出した。POAG発症リスクの指標を緑内障家族歴、進行リスクの指標を緑内障診断時年齢としてGRSとの関係について検討したところ、緑内障家族歴(発症)にはnon-IOP-related遺伝子多型(視神経脆弱性)、緑内障診断時年齢(進行)にはIOP-related遺伝子多型(眼圧上昇)が重要な役割を果たしていることを見出したので報告した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

POAG発症にはnon-IOP-related遺伝子多型、進行にはIOP-related遺伝子多型が重要な役割を果たしていることを見出すことができ、予定通りの進捗状況となっている。

Strategy for Future Research Activity

POAG感受性遺伝子多型解析を進めるとともに、視野検査を含む臨床データの収集を継続して行っていく。IOP-related遺伝子多型、non-IOP-related遺伝子多型に加え、検索したすべてのPOAG感受性遺伝子多型のgenetic risk scoreを算出し、視野障害パターンや進行度、POAG発症リスク評価、眼圧上昇予測、POAG発症年齢予測のための基礎データを構築していく。

Research Products

• [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: Am J Ophthalmol Volume: 212 Pages: 135-140
  • DOI: 10.1016/j.ajo.2020.03.014
  • 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: 10 Pages: 7188-7188
  • DOI: 10.1038/s41598-020-64301-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide association study identifies seven novel susceptibility loei for primary open-angle glaucoma (2018)
  • Author(s): Shiga Y, Akiyama M, Nishiguchi K M, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yanaka T, et al.
  • 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