Identification of locomotive and metabolic syndrome-related genes by genome wide association and functional analysis

• Project/Area Number: 25293214
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The University of Tokyo
• Principal Investigator: Urano Tomohiko 東京大学, 医学部附属病院, 講師 (20334386)
• Co-Investigator(Kenkyū-buntansha): INOUE Satoshi 東京大学, 医学部附属病院, 特任教授 (40251251)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 骨粗鬆症 / サルコペニア / 肥満 / ゲノムワイド解析 / ロコモーティブ症候群 / メタボリック症候群 / 性ホルモン / Wntシグナル

Outline of Final Research Achievements

Osteoporosis is a skeletal disease characterized by an increased susceptibility to fractures. Evidence from genetic analyses indicates that pathogenesis of osteoporosis is genetically controlled. We show that the SLC25A32, the mitochondrial inner membrane folate transporter, gene polymorphism could be a risk factor for lower folate concentration and future fracture. Moreover, we have identified single-nucleotide polymorphisms (SNPs) that are associated with the development of sarcopenia, which is characterized by a loss of lean body mass, and obesity, which is characterized by high fat mass by genome-wide association studies (GWAS). Here, we have shown that GWAS revealed a functional SNP in the 5'-flanking region of PRDM16 gene associated with lean body mass. We also found that genetic analyses in human and knock out mouse models revealed the importance of SLC25A24/Slc25a24 in the regulation of body fat mass and adipogenesis.

Research Products

• [Journal Article] Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal women. (2016)
  • Author(s): Urano T, Shiraki M, Kuroda T, Tanaka S, Uenishi K, Inoue S.
  • Journal Title: J Bone Miner Metab. Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SLC25A24 as a novel susceptibility gene for low fat mass in humans and mice (2015)
  • Author(s): Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S
  • Journal Title: J Clin Endocrinol Metab Volume: 印刷中 Issue: 4 Pages: E655-E663
  • DOI: 10.1210/jc.2014-2829
  • Peer Reviewed
• [Journal Article] Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation with Aberrant Mineralization. (2015)
  • Author(s): Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano T, Horie-Inoue K, Ouchi Y, Amizuka N, Inoue S
  • Journal Title: J Bone Miner Res. Volume: 未定 Issue: 7 Pages: 1245-1254
  • DOI: 10.1002/jbmr.2463
  • Peer Reviewed / Open Access
• [Journal Article] Recent genetic discoveries in osteoporosis, sarcopenia and obesity [Review] (2015)
  • Author(s): Urano T, Inoue S
  • Journal Title: Endocrine Journal Volume: 62 Issue: 6 Pages: 475-484
  • DOI: 10.1507/endocrj.EJ15-0154
  • NAID: 130005085770
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Identification of TRIM22 as a progesterone-responsive gene in Ishikawa endometrial cancer cells. (2015)
  • Author(s): Saito-Kanatani M, Urano T, Hiroi H, Momoeda M, Ito M, Fujii T, Inoue S
  • Journal Title: J Steroid Biochem Mol Biol Volume: 154 Pages: 217-225
  • DOI: 10.1016/j.jsbmb.2015.08.024
  • Peer Reviewed
• [Journal Article] TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. (2015)
  • Author(s): Takayama K, Misawa A, Suzuki T, Takagi K, Hayashizaki Y, Fujimura T, Homma Y, Takahashi S, Urano T, Inoue S
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 8219-8219
  • DOI: 10.1038/ncomms9219
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial. (2015)
  • Author(s): Fujimura T, Takahashi S, Kume H, Urano T, Takayama K, Yamada Y, Suzuki M, Fukuhara H, Nakagawa T, Inoue S, Homma Y.
  • Journal Title: BMC Cancer. Volume: 15 Issue: 1 Pages: 836-836
  • DOI: 10.1186/s12885-015-1871-z
  • Peer Reviewed / Open Access
• [Journal Article] RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer (2015)
  • Author(s): Takayama K, Suzuki T, Tsutsumi S, Fujimura T, Urano T, Takahashi S, Homma Y, Aburatani H, Inoue S
  • Journal Title: Oncotarget Volume: 6 Pages: 2263-2276
  • Peer Reviewed
• [Journal Article] Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women. (2014)
  • Author(s): Urano T, Shiraki M, Saito M, Sasaki N, Ouchi Y, Inoue S
  • Journal Title: Geriatric Gerontol Int Volume: in press Issue: 4 Pages: 942-946
  • DOI: 10.1111/ggi.12201
  • Peer Reviewed
• [Journal Article] Large-scale analysis reveals a functional single-nucleotide polymorphism in the 5'-flanking region of PRDM16 gene associated with lean body mass (2014)
  • Author(s): Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S
  • Journal Title: Aging Cell Volume: 13 Issue: 4 Pages: 739-743
  • DOI: 10.1111/acel.12228
  • Peer Reviewed
• [Journal Article] Survey of the utility of once-monthly bisphosphonate treatment for improvement of medication adherence in osteoporosis patients in Japan. (2014)
  • Author(s): Makita K, Okano H, Furuya T, Urano T, Hirabayashi H, Kumakubo T, Iwamoto J
  • Journal Title: J Bone Miner Metab Volume: in press Issue: 1 Pages: 55-60
  • DOI: 10.1007/s00774-013-0553-7
  • Peer Reviewed
• [Journal Article] CtBP2 modulates the androgen receptor to promote prostate cancer progression (2014)
  • Author(s): Takayama K, Suzuki T, Fujimura T, Urano T, Takahashi S, Homma Y, Inoue S
  • Journal Title: Cancer Res Volume: 74 Issue: 22 Pages: 6542-6553
  • DOI: 10.1158/0008-5472.can-14-1030
  • Peer Reviewed
• [Journal Article] Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth (2014)
  • Author(s): Obinata D, Ito Akiko, Fujiwara K, Takayama K, Ashikari D, Murata Y, Yamaguchi K, Urano T, Fujimura T, Fukuda N, Soma M, Watanabe T, Nagase H, Inoue S, Takahashi S
  • Journal Title: Cancer Sci Volume: 105 Issue: 10 Pages: 1272-1278
  • DOI: 10.1111/cas.12493
  • Peer Reviewed / Open Access
• [Journal Article] Expression of androgen and estrogen signaling components and stem cell markers to predict cancer progression and cancer-specific survival in patients with metastatic prostate cancer (2014)
  • Author(s): Fujimura T, Takahashi S, Urano T, Takayama K, Sugihara T, Obinata D, Yamada Y, Kumagai J, Kume H, Ouchi Y, Inoue S, Homma Y
  • Journal Title: Clin Cancer Res Volume: 20 Issue: 17 Pages: 4625-4635
  • DOI: 10.1158/1078-0432.ccr-13-1105
  • Peer Reviewed
• [Journal Article] Systemic identification of estrogen-regulated genes in breast cancer cells through cap analysis of gene expression mapping (2014)
  • Author(s): Yamaga R, Ikeda K, Boele J, Horie-Inoue K, Takayama K, Urano T, Kaida K, Carninci P, Kawai J, Hayashizaki Y, Ouchi Y, de Hoon M, Inoue S
  • Journal Title: Biochem Biophys Res Commun Volume: 447 Issue: 3 Pages: 531-536
  • DOI: 10.1016/j.bbrc.2014.04.033
  • Peer Reviewed
• [Journal Article] Genetics of osteoporosis. Special issue of “Genomic Aspects of Common Diseases” (2014)
  • Author(s): Urano T, Inoue S
  • Journal Title: Biochem Biophys Res Commun Volume: 452 Issue: 2 Pages: 287-293
  • DOI: 10.1016/j.bbrc.2014.07.141
  • Peer Reviewed
• [Journal Article] Liver-specific γ-glutamyl carboxylase-1 deficient mice display bleeding diathesis and short life span. (2014)
  • Author(s): Azuma K, Tsukui T, Ikeda K, Shiba S, Nakagawa K, Okano T, Urano T, Horie-Inoue K, Ouchi Y, Ikawa M, Inoue S
  • Journal Title: PLoS ONE Volume: 9 Issue: 2 Pages: e88643-e88643
  • DOI: 10.1371/journal.pone.0088643
  • Peer Reviewed
• [Journal Article] Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. (2013)
  • Author(s): Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, Homma Y, Ouchi Y, Aburatani H, Hayashizaki Y, Inoue S
  • Journal Title: EMBO J Volume: 32 Issue: 12 Pages: 1665-1680
  • DOI: 10.1038/emboj.2013.99
  • Peer Reviewed
• [Journal Article] Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor. (2013)
  • Author(s): Yamada Y, Fujimura T, Takahashi S, Takayama K, Urano T, Murata T, Obinata D, Ouchi Y, Homma Y, Inoue S
  • Journal Title: Adv Urol Volume: 2013 Pages: 348438-348438
  • DOI: 10.1155/2013/348438
  • Peer Reviewed
• [Presentation] 「ロコモティブシンドロームと骨粗鬆症の現状、そして栄養の課題-老年症候群および骨粗鬆症について」 (2015)
  • Author(s): 浦野友彦
  • Organizer: 第62回日本栄養改善学会
  • Place of Presentation: 福岡国際会議場 (福岡県福岡市)
  • Year and Date: 2015-09-24
  • Invited
• [Presentation] 5年間の選択的エストロゲン受容体モジュレーター治療が体格に与える影響 (2015)
  • Author(s): 浦野友彦、白木正孝、田中司朗、黒田龍彦、井上聡
  • Organizer: 第17回日本骨粗鬆症学会
  • Place of Presentation: 広島国際会議場 (広島県広島市)
  • Year and Date: 2015-09-17
• [Presentation] [ワークショップ] ゲノムワイド解析から捉える老年病と運動器の老化を制御する分子機構 (Genome-wide association studies identify novel genes associated with locomotive and geriatric syndrome) (2014)
  • Author(s): 浦野友彦、井上聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] アンドロゲン応答性の脂質代謝酵素ACSL3 は去勢抵抗性前立腺がんの増殖に関与する (Androgen-responsive and lipogenic enzyme ACSL3 is involved in castration-resistant growth of prostate cancer) (2014)
  • Author(s): 右田敏郎、高山賢一、大日方大亮、池田和貴、浦野友彦、高橋悟、曽我朋義、井上聡
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] [シンポジウム] 東京大学医学部附属病院老年病科病棟における高齢者診療の取り組み (2014)
  • Author(s): 浦野友彦、秋下雅弘
  • Organizer: 第60回日本老年医学会関東甲信越地方会
  • Place of Presentation: 杏林大学医学部付属病院（東京都・三鷹市）
  • Year and Date: 2014-09-20
• [Presentation] LOH 症候群の一例 (2014)
  • Author(s): 七尾道子、小島太郎、浦野友彦、山口泰弘、小川純人、秋下雅弘
  • Organizer: 第60回日本老年医学会関東甲信越地方会
  • Place of Presentation: 杏林大学医学部付属病院（東京都・三鷹市）
  • Year and Date: 2014-09-20
• [Presentation] [若手シンポジウム] ロコモティブ症候群ならびにメタボリック症候群における疾患関連遺伝子の探索と同定 (2014)
  • Author(s): 浦野友彦
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-07-24 – 2014-07-26
• [Presentation] [Basic Science 1] ゲノムワイド解析によるアンチエイジング医学関連遺伝子の探索と同定 (2014)
  • Author(s): 浦野友彦、井上聡
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-06-06 – 2014-06-08
• [Presentation] Expression of androgen and estrogen signaling components and stem cell markers predict cancer progression and cancer-specific survival in patients with metastatic prostate cancer. (2014)
  • Author(s): Fujimura T, Takahashi S, Urano T, Kume H, Takayama K, Murata T, Yamada Y, Obinata D, Inoue S, Homma Y
  • Organizer: 109th American Urological Association Annual Meeting
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] ChIP-sequence法の活用による前立腺癌細胞における新たなアンドロゲン受容体シグナルの同定 (2014)
  • Author(s): 芦苅大作、高山賢一、浦野友彦、大日方大亮、井上聡、高橋悟
  • Organizer: 第102回日本泌尿器科学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2014-04-24 – 2014-04-27
• [Presentation] ピロール・イミダゾール・ポリアミド(PIP)を用いた前立腺癌関連融合遺伝子の発現抑制法の検討 (2014)
  • Author(s): 藤原恭子、大日方大亮、伊藤亜希子、高山賢一、浦野友彦、井上聡、相馬正義、高橋悟、永瀬浩喜、福田昇
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Expression of androgen and estrogen signaling components and stem cell markers is highly predictive of cancer progression of metastatic prostate cancer. (2014)
  • Author(s): Fujimura T, Takahashi S, Urano T, Kume H, Takayama K, Murata T, Yamada Y, Obinata D, Inoue S, Homma Y
  • Organizer: 29th Annual Congress of the European Association of Urology
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-04-11 – 2014-04-15
• [Presentation] Polyamide targeting transcription of long chain acyl-CoA synthetase 3: A novel therapeutic approach for prostate cancer. (2014)
  • Author(s): Obinata D, Takayama K, Fujiwara K, Fukuda N, Urano T, Ito A, Ashikari D, Murata T, Fujimura T, Ikeda K, Horie-Inoue K, Inoue S, Takahashi S
  • Organizer: 29th Annual Congress of the European Association of Urology
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-04-11 – 2014-04-15
• [Presentation] [研究奨励賞] 骨粗鬆症ならびに乳癌における液性因子から受容体を介した新規病態メカニズムの探索と同定 (2013)
  • Author(s): 浦野友彦
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] ヒトならびにマウスにおいて体脂肪量の制御に関与するミトコンドリアトランスポーター遺伝子の同定 (2013)
  • Author(s): 浦野友彦、白木正孝、大内尉義、井上聡：
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] 前立腺癌細胞におけるアンドロゲン応答性Non-coding RNAの同定ならびに機能解析 (2013)
  • Author(s): 高山賢一、堀江公仁子、池田和博、浦野友彦、大内尉義、井上聡：
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] プロゲステロン受容体PRAおよびPRB高発現子宮内膜癌細胞株を用いたプロゲステロン応答遺伝子の包括的探索 (2013)
  • Author(s): 齋藤真由子、浦野友彦、廣井久彦、伊藤正典、中江華子、百枝幹夫、藤井知行、上妻志郎、井上聡
  • Organizer: 第65回日本産科婦人科学会学術講演会
  • Place of Presentation: 札幌
• [Presentation] [研究奨励賞受賞講演] ヒト遺伝子解析・マウスモデル・細胞モデルを用いた骨粗鬆症の診断ならびに治療標的の探索と同定 (2013)
  • Author(s): 浦野友彦
  • Organizer: 国際骨代謝学会・日本骨代謝学会第2回合同会議
  • Place of Presentation: 神戸
• [Presentation] ヒトにおいて筋肉量の制御に関与する遺伝子の探索と同定 (2013)
  • Author(s): 浦野友彦、白木正孝、大内尉義、井上聡
  • Organizer: 国際骨代謝学会・日本骨代謝学会第2回合同会議
  • Place of Presentation: 神戸
• [Presentation] 核内受容体SXR/PXRを介するビタミンKの関節軟骨に対する作用 (2013)
  • Author(s): 東浩太郎、Stephanie Casey、浦野友彦、大内尉義、Bruce Blumberg、井上聡
  • Organizer: 第55回日本老年医学会学術集会
  • Place of Presentation: 大阪
• [Presentation] 前立腺癌におけるEstrogen-responsive finger proteinの機能に関する検討 (2013)
  • Author(s): 浦野友彦、大内尉義、井上聡：
  • Organizer: 第13回日本抗加齢医学会総会
  • Place of Presentation: 横浜
• [Presentation] Novel collaborating factors for androgen receptor form transcriptional networks and contribute to the progression of prostate cancer (2013)
  • Author(s): 高山賢一、浦野友彦、井上聡：
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] ゲノムワイド解析による骨量ならびに脂肪量規定因子の探索 (2013)
  • Author(s): 浦野友彦、白木正孝、大内尉義、井上聡
  • Organizer: 第15回日本骨粗鬆症学会
  • Place of Presentation: 大阪
• [Presentation] Identification of a single nucleotide polymorphism in the 5'-flanking region of PRDM16 gene as a novel susceptibility marker for low lean body mass (2013)
  • Author(s): Urano T, Shiraki M, Ouchi Y, Inoue S
  • Organizer: American Society of Bone and Mineral Research 35th Annual Meeting
  • Place of Presentation: Baltimore, Maryland, USA