International collaboration on the research of novel urate transporters by leveraging genetic differences between the Japanese and the Czech

• Project/Area Number: 18KK0247
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: TAKADA Tappei 東京大学, 医学部附属病院, 講師 (90376468)
• Co-Investigator(Kenkyū-buntansha): 市田 公美 東京薬科大学, 薬学部, 教授 (80183169) ; 松尾 洋孝 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 分子生体制御学, 准教授 (00528292) ; 豊田 優 東京大学, 医学部附属病院, 届出研究員 (80650340)
• Project Period (FY): 2018-10-09 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2019: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 尿酸 / 遺伝子多型 / トランスポーター / 人種差 / 国際共同研究

Outline of Final Research Achievements

By a series of in vitro experiments and clinical analyses including international collaborations, we revealed that 1) there were clinically-relevant rare dysfunctional variants of ABCG2 in a gout and hyperuricemia cohort, 2) there were novel loci which aggravate asymptomatic hyperuricemia into gout revealed by genome-wide association studies, 3) familial early-onset hyperuricemia and gout associated with dysfunctional variants of ABCG2, 4) there were subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients.

Academic Significance and Societal Importance of the Research Achievements

本国際共同研究で得られた研究成果は、痛風、高尿酸血症をはじめとするさまざまな尿酸関連疾患の予防・治療戦略の立案に役立つことが期待される。例えば、より精度の高い遺伝子診断による各種疾患のリスク予測などに貢献しうるものであり、今後、応用研究や社会実装も見据えた研究のさらなる発展が期待される。

Research Products

• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Int'l Joint Research] University of Otago(ニュージーランド)
• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Int'l Joint Research] University of Otago(ニュージーランド)
• [Int'l Joint Research] Charles University in Prague/Institute of Rheumatology, Prague(チェコ)
• [Journal Article] Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A12 (2021)
  • Author(s): Toyoda Yu、Kawamura Yusuke、Nakayama Akiyoshi、Nakaoka Hirofumi、Higashino Toshihide、Shimizu Seiko、Ooyama Hiroshi、Morimoto Keito、Uchida Naohiro、Shigesawa Ryuichiro、Takeuchi Kenji、Inoue Ituro、Ichida Kimiyoshi、Suzuki Hiroshi、Shinomiya Nariyoshi、Takada Tappei、Matsuo Hirotaka
  • Journal Title: Rheumatology Volume: - Issue: 11 Pages: 5224-5232
  • DOI: 10.1093/rheumatology/keab327
  • Peer Reviewed / Open Access
• [Journal Article] Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2. (2021)
  • Author(s): Taniguchi T, Omura K, Motoki K, Sakai M, Chikamatsu N, Ashizawa N, Takada T, Iwanaga T.
  • Journal Title: Sci Rep. Volume: 11(1) Issue: 1 Pages: 7232-7232
  • DOI: 10.1038/s41598-021-86662-9
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout. (2021)
  • Author(s): Toyoda Y, Pavelcova K, Bohata J, Jesina P, Kubota Y, Suzuki H, Takada T, Stiburkova B.
  • Journal Title: Int J Mol Sci. Volume: 22(4) Issue: 4 Pages: 1935-1935
  • DOI: 10.3390/ijms22041935
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a dysfunctional splicing mutation in the SLC22A12/URAT1 gene causing renal hypouricaemia type 1: a report on two families (2020)
  • Author(s): Kawamura Yusuke、Toyoda Yu、Ohnishi Takuma、Hisatomi Ryutaro、Higashino Toshihide、Nakayama Akiyoshi、Shimizu Seiko、Yanagi Masato、Kamimaki Isamu、Fujimaru Rika、Suzuki Hiroshi、Shinomiya Nariyoshi、Takada Tappei、Matsuo Hirotaka
  • Journal Title: Rheumatology Volume: 59 Issue: 12 Pages: 3988-3990
  • DOI: 10.1093/rheumatology/keaa461
  • Peer Reviewed / Open Access
• [Journal Article] Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice. (2020)
  • Author(s): Toyoda Y, Takada T, Miyata H, Matsuo H, Kassai H, Nakao K, Nakatochi M, Kawamura Y, Shimizu S, Shinomiya N, Ichida K, Hosoyamada M, Aiba A, Suzuki H
  • Journal Title: Proc. Natl.Acad. Sci. USA Volume: 117 Issue: 31 Pages: 18175-18177
  • DOI: 10.1073/pnas.2006958117
  • Peer Reviewed / Open Access
• [Journal Article] Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients (2020)
  • Author(s): Nakashima Akio、Ichida Kimiyoshi、Ohkido Ichiro、Yokoyama Keitaro、Matsuo Hirotaka、Ohashi Yuki、Takada Tappei、Nakayama Akiyoshi、Suzuki Hiroshi、Shinomiya Nariyoshi、Urashima Mitsuyoshi、Yokoo Takashi
  • Journal Title: Human Cell Volume: epub ahead of print Issue: 3 Pages: 1-10
  • DOI: 10.1007/s13577-020-00342-w
  • Peer Reviewed / Open Access
• [Journal Article] Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients. (2020)
  • Author(s): Nakayama A, Takada T, et al.
  • Journal Title: Ann Rheum Dis. Volume: 79 Issue: 5 Pages: 657665-657665
  • DOI: 10.1136/annrheumdis-2019-216644
  • NAID: 120007042436
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber (2020)
  • Author(s): Saito Hiroki、Toyoda Yu、Takada Tappei、Hirata Hiroshi、Ota-Kontani Ami、Miyata Hiroshi、Kobayashi Naoyuki、Tsuchiya Youichi、Suzuki Hiroshi
  • Journal Title: Nutrients Volume: 12 Issue: 6 Pages: 1601-1601
  • DOI: 10.3390/nu12061601
  • Peer Reviewed / Open Access
• [Journal Article] Higher blood uric acid in female humans and mice as a protective factor against pathophysiological decline of lung function (2020)
  • Author(s): Fujikawa H, Sakamoto Y, Masuda N, Oniki K, Kamei S, Nohara H, Nakashima R, Maruta K, Kawakami T, Eto Y, Takahashi N, Takeo T, Nakagata N, Watanabe H, Otake K, Ogata Y, Tomioka NH, Hosoyamada M, Takada T, Ueno-Shuto K , Suico MA, Kai H, Saruwatari J, Shuto T.
  • Journal Title: Antioxidants Volume: 9 Issue: 5 Pages: 387-387
  • DOI: 10.3390/antiox9050387
  • URL: https://localhost/en/publications/7499b061-83b6-4e0b-91f6-bb12a5798316
  • Peer Reviewed / Open Access
• [Journal Article] A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population. (2020)
  • Author(s): Akashi A, Nakayama A, Kamatani Y, Higashino T, Shimizu S, Kawamura Y, Imoto M, Naito M, Hishida A, Kawaguchi M, Takao M, Matsuo M, Takada T, Ichida K, Ooyama H, Shinomiya N, Matsuo H.
  • Journal Title: Hum Cell. Volume: 33 Issue: 2 Pages: 303307-303307
  • DOI: 10.1007/s13577-019-00318-5
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of Citrus flavonoids on the in vitro transport activity of human urate transporter 1 (URAT1/SLC22A12), a renal re-absorber of urate. (2020)
  • Author(s): Toyoda Y, Takada T, Saito H, Hirata H, Ota-Kontani A, Kobayashi N, Tsuchiya Y, Suzuki H.
  • Journal Title: NPJ Sci Food. Volume: 4 Issue: 1 Pages: 3-3
  • DOI: 10.1038/s41538-020-0063-7
  • Peer Reviewed / Open Access
• [Journal Article] Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. (2020)
  • Author(s): Higashino T, Morimoto K, Nakaoka H, Toyoda Y, Kawamura Y, Shimizu S, Nakamura T, Hosomichi K, Nakayama A, Ooyama K, Ooyama H, Shimizu T, Ueno M, Ito T, Tamura T, Naito M, Nakashima H, Kawaguchi M, Takao M, Kawai Y, Osada N, Ichida K, Yamamoto K, Suzuki H, Shinomiya N, Inoue I, Takada T, Matsuo H.
  • Journal Title: Ann Rheum Dis. Volume: 79(1) Issue: 1 Pages: 164-166
  • DOI: 10.1136/annrheumdis-2019-216044
  • Peer Reviewed / Open Access
• [Journal Article] Familial early-onset hyperuricemia and gout associated with a newly identified dysfunctional variant in urate transporter ABCG2. (2019)
  • Author(s): Toyoda Y, Pavelcova K, Klein M, Suzuki H, Takada T, Stiburkova B.
  • Journal Title: Arthritis Res Ther. Volume: 21(1) Issue: 1 Pages: 219-219
  • DOI: 10.1186/s13075-019-2007-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout (2019)
  • Author(s): Kawamura Y, Nakaoka H, Nakayama A, et al.
  • Journal Title: Ann Rheum Dis Volume: 78 Issue: 10 Pages: 1430-1437
  • DOI: 10.1136/annrheumdis-2019-215521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort (2019)
  • Author(s): Toyoda Yu, Mancikova Andrea, Krylov Vladimir, Morimoto Keito, Pavelcova Katerina, Bohata Jona, Pavelka Karel, Pavlikova Marketa, Suzuki Hiroshi, Matsuo Hirotaka, Takada Tappei, Stiburkova Blanka
  • Journal Title: Cells Volume: 8 Issue: 4 Pages: 363-363
  • DOI: 10.3390/cells8040363
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications. (2019)
  • Author(s): Toyoda Y, Takada T, Suzuki H.
  • Journal Title: Front Pharmacol. Volume: 10 Pages: 208-208
  • DOI: 10.3389/fphar.2019.00208
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Osthol Isolated from Cnidium monnieri Fruit on Urate Transporter 1. (2018)
  • Author(s): Tashiro Y, Sakai R, Hirose-Sugiura T, Kato Y, Matsuo H, Takada T, Suzuki H, Makino T.
  • Journal Title: Molecules. Volume: 23(11) Issue: 11 Pages: 2837-2837
  • DOI: 10.3390/molecules23112837
  • Peer Reviewed / Open Access
• [Journal Article] Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression. (2018)
  • Author(s): Takada T, Yamamoto T, Matsuo H, Tan JK, Ooyama K, Sakiyama M, Miyata H, Yamanashi Y, Toyoda Y, Higashino T, Nakayama A, Nakashima A, Shinomiya N, Ichida K, Ooyama H, Fujimori S, Suzuki H
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11147-11147
  • DOI: 10.1038/s41598-018-29208-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] トランスポーターによる尿酸動態制御 (2021)
  • Author(s): 高田龍平、松尾洋孝、市田公美
  • Organizer: 第54回日本痛風・尿酸核酸学会総会（web）
  • Invited
• [Presentation] Functional Cooperation of Physiological Urate Transporters and Their Modification by Food Components (2020)
  • Author(s): Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, et al.
  • Organizer: JAACT2020 Fuchu（web）
  • Int'l Joint Research / Invited
• [Presentation] ゲノム解析により見出された尿酸トランスポーターと尿酸降下薬に関する研究 (2020)
  • Author(s): 高田龍平、豊田優、他
  • Organizer: 第30回日本医療薬学会年会（web）
  • Invited
• [Presentation] ABCG2, a physiologically and pharmacologically important exporter in humans (2020)
  • Author(s): Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, et al.
  • Organizer: 8th FEBS Special Meeting: ABC Proteins - from Genetic Disease to Multidrug Resistance
  • Int'l Joint Research / Invited
• [Presentation] 尿酸排出トランスポーターによる尿酸動態制御メカニズムの解析 (2020)
  • Author(s): 高田龍平
  • Organizer: 第53回日本痛風・尿酸核酸学会総会
  • Invited
• [Presentation] ABCG2 transports urate and uremic toxin indoxyl sulfate and influences CKD progression (2019)
  • Author(s): Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, et al.
  • Organizer: Asia-Pacific Gout Consortium 3rd Annual Meeting (APGC 2019)
  • Int'l Joint Research / Invited
• [Presentation] Urate transporter ABCG2 is a physiological exporter of uremic toxin indoxyl sulfate and a crucial factor influencing CKD progression (2019)
  • Author(s): Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, et al.
  • Organizer: 18th International Symposium on Purine and Pyrimidine Metabolism in Man
  • Int'l Joint Research / Invited
• [Presentation] 腸管・腎尿細管の尿酸輸送と高尿酸血症 (2019)
  • Author(s): 高田龍平、豊田優、他
  • Organizer: 第50回日本消化吸収学会総会
  • Invited
• [Presentation] 尿酸排出トランスポーターABCG2に関する生理学的・薬理学的研究 (2019)
  • Author(s): 高田龍平、豊田優、他
  • Organizer: 生理研研究会『上皮膜・間質の機能連関と病態発現機構解明のためのストラテジー』
  • Invited
• [Presentation] 微粒子形成の予防～尿酸動態制御と薬物治療について～ (2019)
  • Author(s): 高田龍平、他
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] Molecular functional analyses of transporters related to "urate transport disorders" (2018)
  • Author(s): Tappei Takada, et al.
  • Organizer: Joint Conference of the 2nd Asia-Pacific Gout Consortium (APGC) and the 8th Oriental Gout Forum
  • Int'l Joint Research / Invited
• [Presentation] Pathophysiological metabolome analysis of ABCG2 transporter (2018)
  • Author(s): Tappei Takada, et al.
  • Organizer: International Meeting on 22nd MDO and 33rd JSSX
  • Int'l Joint Research / Invited
• [Presentation] Reverse translational research on membrane transporters (2018)
  • Author(s): Tappei Takada
  • Organizer: 18th World Congress of basic and clinical Pharmacology (WCP2018)
  • Int'l Joint Research / Invited
• [Presentation] 生活習慣病とトランスポーターに関する研究～病院薬剤師の視点から～ (2018)
  • Author(s): 高田龍平
  • Organizer: 第7回 BRIGHT symposium
  • Invited
• [Presentation] 血清尿酸値変動薬と尿酸排出トランスポーターABCG2の相互作用に関する研究 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 第40回生体膜と薬物の相互作用シンポジウム
• [Presentation] 尿酸排出輸送体ABCG2による尿酸動態制御機構の解明 (2018)
  • Author(s): 高田龍平
  • Organizer: 第29回痛風研修会
  • Invited
• [Presentation] 尿酸排出トランスポーターABCG2による血清尿酸値制御 (2018)
  • Author(s): 高田龍平、他
  • Organizer: 生理研研究会『体内環境の維持機構における上皮膜輸送の多角的・統合的理解』
  • Invited
• [Book] 電気泳動（痛風病因としての尿酸トランスポーターABCG2の病態生理学的重要性とレアバリアント解析） (2021)
  • Author(s): 豊田優、高田龍平、松尾洋孝、市田公美、Blanka Stiburkova、鈴木洋史
  • Publisher: 日本電気泳動学会
• [Book] 痛風と核酸代謝（血清尿酸値変動薬が尿酸輸送体ABCG2に与える影響の検討） (2018)
  • Author(s): 高田龍平、松尾洋孝、市田公美
  • Total Pages: 2
  • Publisher: 日本痛風・核酸代謝学会
• [Book] 痛風と核酸代謝（尿酸トランスポーター遺伝子ABCG2のレアバリアントはコモンバリアントと同様に痛風のリスクを著しく上昇させる） (2018)
  • Author(s): 松尾洋孝、東野俊英、高田龍平、清水聖子、川口真、崎山真幸、中山昌喜、河村優輔、細谷龍男、市田公美、大山博司、鈴木洋史、四ノ宮成祥
  • Total Pages: 1
  • Publisher: 日本痛風・核酸代謝学会
• [Book] 痛風と核酸代謝（CKD患者の腎機能低下に及ぼす尿酸トランスポーターABCG2の保護的役割の解明） (2018)
  • Author(s): 三輪裕幸、内田俊也、柴田茂、高田龍平、松尾洋孝、市田公美
  • Total Pages: 1
  • Publisher: 日本痛風・核酸代謝学会
• [Remarks] 自己紹介（研究室ホームページ内）
  • URL: http://plaza.umin.ac.jp/~todaiyak/t_takada.php