Practical application to preventive medicine by molecular epidemiological analyses on gout using international consortium framework from Japan

• Project/Area Number: 17H04128
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Epidemiology and preventive medicine
• Research Institution: National Defense Medical College
• Principal Investigator: Matsuo Hirotaka 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)
• Co-Investigator(Kenkyū-buntansha): 山本 健 久留米大学, 医学部, 教授 (60274528) ; 中村 好宏 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, 進学課程, 准教授 (60415255)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 痛風 / 高尿酸血症 / 尿酸トランスポーター / 遺伝子 / 国際コンソーシアム / 予防医学 / 個別化医療 / 尿酸輸送体

Outline of Final Research Achievements

Gout/hyperuricemia is one of lifestyle diseases and is also a risk of hypertension, kidney disease, and stroke. Recent genetic studies implied that genetic factors rather than environmental factors have strong effect as its cause. We have developed Asian international consortium named “AsiaGout” and conducted several researches for the practical application to preventive medicine by molecular pathophysiological analyses on gout with other international consortiums. As results, we have identified many disease-associated loci and revealed that Japanese has evolved to have greater genetic effect on the onset of gout. The present research will be helpful to develop genome-personalized preventive method from Japan, as it leads multifactorial disorders including lifestyle diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究では世界最大規模の患者集団の解析を通して、痛風に関連する数多くの遺伝子座と変異の性質が調べられた。さらにアジア国際コンソーシアム”AsiaGout”に加え、より大きな国際コンソーシアムAPGC (Asia Pacific Gout Consortium)も設立され、令和元年7月に研究代表者が大会長として東京で年会を主催した。この国際共同研究の成果として、新規痛風遺伝子座の同定に加え、痛風発症について日本人が遺伝的に影響を受けやすく適応進化した遺伝子座も見出している。このように、本研究はゲノム個別化医療に寄与する、痛風・尿酸関連疾患の分子疫学を日本がリードして進展させる学術的成果を挙げた。

Research Products

• [Int'l Joint Research] チンタオ大学/高雄大学(中国)
• [Int'l Joint Research] オタゴ大学(ニュージーランド)
• [Int'l Joint Research] プラハ大学(チェコ)
• [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] 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] 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] Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. (2019)
  • Author(s): Nakatochi M, Kanai M, Nakayama A, Hishida A, Kawamura Y, Ichihara S, Akiyama M, Ikezaki H, Furusyo N, Shimizu S, Yamamoto K, et al.
  • Journal Title: Commun Biol. Volume: 2 Issue: 1 Pages: 115-115
  • DOI: 10.1038/s42003-019-0339-0
  • NAID: 120006937615
  • Peer Reviewed / Open Access
• [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] Common variant of BCAS3 is associated with gout risk in Japanese population: the first replication study after gout GWAS in Han Chinese. (2018)
  • Author(s): Sakiyama M, Matsuo H, Nakaoka H, Kawamura Y, Kawaguchi M, Higashino T, Nakayama A, Akashi A, Ueyama J, Kondo T, Wakai K, Sakurai Y, Yamamoto K, Ooyama H, Shinomiya N.
  • Journal Title: BMC Med Genet. Volume: 19 Issue: 1 Pages: 96-96
  • DOI: 10.1186/s12881-018-0583-z
  • Peer Reviewed / Open Access
• [Journal Article] A common variant of MAF/c-MAF, transcriptional factor gene in the kidney, is associated with gout susceptibility. (2018)
  • Author(s): Higashino T, Matsuo H, Okada Y, Nakashima H, Shimizu S, Sakiyama M, Tadokoro S, Nakayama A, Kawaguchi M, Komatsu M, Hishida A, Nakatochi M, Ooyama H, Imaki J, Shinomiya N.
  • Journal Title: Human Cell Volume: 31 Issue: 1 Pages: 10-13
  • DOI: 10.1007/s13577-017-0186-6
  • Peer Reviewed / Open Access
• [Journal Article] Independent effects of ADH1B and ALDH2 common dysfunctional variants on gout risk. (2017)
  • Author(s): Sakiyama M, Matsuo H, Akashi A, Shimizu S, Higashino T, Kawaguchi M, Nakayama A, Naito M, Kawai S, Nakashima H, Sakurai Y, Ichida K, Shimizu T, Ooyama H, Shinomiya N.
  • Journal Title: Scientific Report Volume: 7 Issue: 1 Pages: 2500-2500
  • DOI: 10.1038/s41598-017-02528-z
  • Peer Reviewed / Open Access
• [Journal Article] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. (2017)
  • Author(s): Nakayama A, Nakaoka H, Yamamoto K, Sakiyama M, Shaukat A, Toyoda Y, Okada Y, Ohkawa Y,他39名
  • Journal Title: Ann Rheum Dis. Volume: 76 Issue: 5 Pages: 869-877
  • DOI: 10.1136/annrheumdis-2016-209632
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple common and rare variants of ABCG2 cause gout (2017)
  • Author(s): Higashino Toshihide、Takada Tappei、Nakaoka Hirofumi、Toyoda Yu、Stiburkova Blanka、Miyata Hiroshi、Ikebuchi Yuki、Nakashima Hiroshi、Shimizu Seiko、Kawaguchi Makoto、Sakiyama Masayuki、Nakayama Akiyoshi、Akashi Airi、Tanahashi Yuki、Kawamura Yusuke、Nakamura Takahiro、Wakai Kenji、Hosomichi Kazuyoshi 他
  • Journal Title: RMD Open Volume: 3 Issue: 2 Pages: e000464-e000464
  • DOI: 10.1136/rmdopen-2017-000464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] URAT2/OAT10遺伝子の機能低下型ミスセンスSNPは血清尿酸値と痛風のリスクを共に低下させる. (2020)
  • Author(s): 河村優輔, 東野俊英, 清水聖子 他.
  • Organizer: 第53回日本痛風・核酸代謝学会総会.
• [Presentation] 多様なリガンドのエンドサイトーシスに関わる分子LRP2の一塩基多型rs2544390は痛風発症と関連する：日本人男性における痛風とrs2544390のメタ解析. (2020)
  • Author(s): 赤司藍理、中山昌喜、東野俊英 他.
  • Organizer: 第53回日本痛風・核酸代謝学会総会
• [Presentation] ゲノムワイド関連解析による無症候性高尿酸血症患者からの痛風発症に関連する新規遺伝子座の同定. (2020)
  • Author(s): 松尾洋孝、河村優輔、中岡博史 他.
  • Organizer: 第30回日本疫学会学術集会
• [Presentation] 日本人における尿酸値のGWASメタ解析: 尿酸値に関わるアレルで制御される遺伝子はtransport関連遺伝子に集約. (2019)
  • Author(s): 青柳有香, 中杤昌弘, 金井仁弘 他.
  • Organizer: 第12回トランスポーター研究会年会
• [Presentation] Genome-wide meta-analysis revealed multiple novel loci associated with serum uric acid levels in Japanese. (2019)
  • Author(s): Matsuo H, Nakatochi M, Kanai M et al.
  • Organizer: European Congress of Rheumatology.
  • Int'l Joint Research
• [Presentation] Multiple novel loci are associated with serum uric acid levels in Japanese population: a genome-wide meta-analysis. (2019)
  • Author(s): Nakayama A, Nakatochi M, Kanai M et al.
  • Organizer: 18th International Purine and Pyrimidine Symposium.
  • Int'l Joint Research
• [Presentation] 日本人121,745人を対象としたゲノムワイドメタ解析により血清尿酸値と関連する8つの新規遺伝子座を同定した. (2019)
  • Author(s): 中杤昌弘, 松尾洋孝, 中山昌喜, 他.
  • Organizer: 第52回日本痛風核酸代謝学会
• [Presentation] 日本人における尿酸のGWASメタ解析による8個の新規遺伝子座の同定. (2019)
  • Author(s): 中嶌真由子, 中杤昌弘, 金井仁弘 他.
  • Organizer: 第64回防衛衛生学会.
• [Presentation] 高尿酸血症を痛風発症へと増悪させる遺伝要因：ゲノムワイド関連解析から見出された新規遺伝子座. (2019)
  • Author(s): 河村優輔, 中岡博史, 中山昌喜 他.
  • Organizer: 第64回日本人類遺伝学会
• [Presentation] 無症候性高尿酸血症患者が痛風を発症する遺伝的要因：ゲノムワイド関連解析により同定した新規遺伝子座. (2019)
  • Author(s): 河村優輔, 松尾洋孝, 中岡博史 他.
  • Organizer: 第37回日本ヒト細胞学会学術集会.
• [Presentation] A genome-wide association study identified novel loci associated with the aggravation from asymptomatic hyperuricemia to gout. (2019)
  • Author(s): Kawamura Y, Nakaoka H, Nakayama A et al.
  • Organizer: Asia-Pacific Gout Consortium 2nd Annual Meeting.
  • Int'l Joint Research
• [Presentation] A genome-wide association study identified novel loci associated with the progression from asymptomatic hyperuricemia to gout. (2019)
  • Author(s): Kawamura Y, Nakaoka H, Nakayama A et al.
  • Organizer: European Congress of Rheumatology.
  • Int'l Joint Research
• [Presentation] 無症候性高尿酸血症群と痛風症例群のゲノムワイド関連解析により痛風発症に関連する新規遺伝子座を同定した. (2019)
  • Author(s): 河村優輔, 松尾洋孝, 中山昌喜 他.
  • Organizer: 第52回日本痛風核酸代謝学会
• [Remarks] 防衛医科大学校分子生体制御学講座ホームページ
  • URL: http://ndmc-ipb.browse.jp/
• [Patent(Industrial Property Rights)] 1 (2017)
  • Inventor(s): 2017
  • Industrial Property Rights Holder: 2017
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
• [Funded Workshop] Asia-Pacific Gout Consortium 3rd Annual Meeting (APGC2019) (2019)