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Identification of genetic susceptibility to urate-related diseases which is characteristic to Japanese and exploration of its preventive method through molecular genetic-epidemiological analyses

Research Project

Project/Area Number 20K23152
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0908:Society medicine, nursing, and related fields
Research InstitutionNational Defense Medical College

Principal Investigator

Nakayama Akiyoshi  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, 講師 (50876000)

Project Period (FY) 2020-09-11 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsゲノム個別化医療 / 痛風・高尿酸血症・低尿酸血症 / 痛風の病型分類 / 女性痛風 / ゲノムワイド関連解析(GWAS) / 次世代シーケンサー(NGS) / 痛風・高尿酸血症 / ゲノムワイド関連解析 / 次世代シーケンサー / 腎性低尿酸血症
Outline of Research at the Start

痛風や高尿酸血症は、特に日本人において遺伝的要因が強い。また遺伝性疾患である腎性低尿酸血症は日本人で頻度が高い。しかし、現状ではなぜ日本人はこれらの尿酸関連疾患にかかりやすいのか不明である。申請者はこれまでに日本人男性における痛風・高尿酸血症のゲノムワイド関連解析(GWAS)を多数報告し、また、腎性低尿酸血症の診療ガイドラインを策定するなど幅の広い研究を行ってきた。本研究では、痛風症例の病型分類別のGWASと、女性痛風症例のGWAS、そして腎性低尿酸血症症例の次世代シーケンサー解析を計画しており、日本人に特徴的な尿酸関連疾患の個人差を同定し、この個人差に基づく新規予防法を探索する。

Outline of Final Research Achievements

We revealed novel gout loci from genome-wide association analyses (GWASs) with gout subtypes and reported a selection pressure on gout susceptibility in Japanese population. Furthermore, we conducted X-chromosome-wide association analyses on serum urate levels, inter-subtype GWASs on gout, and international collaborative meta-analysis of gout GWASs. Genetic analyses on female gout cases and analyses using next generation sequencer on renal hypouricemia (RHUC) were performed and their results are now under evaluation. Large-scaled analyses with health-check participants enabled accurate evaluation on frequencies and causal variants’ effect of RHUC, resulting in strong genetic evidences which could bring revisions of the present clinical practice guideline for RHUC.

Academic Significance and Societal Importance of the Research Achievements

生活習慣病である痛風・高尿酸血症は、特に日本人において遺伝的要因が強い影響力を持つことが明らかとなってきた。また近年の疫学研究から、これらの疾患は慢性腎臓病や脳・心血管疾患との関連も示唆されるようになった。さらに、遺伝性疾患である腎性低尿酸血症は日本人で頻度が高い。本研究により痛風や高尿酸血症、低尿酸血症といった尿酸関連疾患の分子遺伝疫学的背景を明らかにすることは、病態解明に有用であるだけでなく、日本人に特徴的な尿酸関連疾患の個人差を同定し、それに基づくゲノム個別化医療としての新規治療法や予防法の開発につながることが期待できる。

Report

(3 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (30 results)

All 2022 2021 2020 Other

All Journal Article (11 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 11 results,  Open Access: 11 results) Presentation (18 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] A meta-analysis of genome-wide association studies using Japanese and Taiwanese has revealed novel loci associated with gout susceptibility2022

    • Author(s)
      Chang Shun-Jen、Toyoda Yu、Kawamura Yusuke、Nakamura Takahiro、Nakatochi Masahiro、Nakayama Akiyoshi、et al.
    • Journal Title

      Human Cell

      Volume: 35 Issue: 2 Pages: 767-770

    • DOI

      10.1007/s13577-021-00665-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome-wide meta-analysis between renal overload type and renal underexcretion type of clinically defined gout in Japanese populations2022

    • Author(s)
      Toyoda Yu、Nakayama Akiyoshi、Nakatochi Masahiro、Kawamura Yusuke、Nakaoka Hirofumi、Yamamoto Ken、Shimizu Seiko、Ooyama Hiroshi、Ooyama Keiko、Shimizu Toru、Nagase Mitsuo、Hidaka Yuji、Ichida Kimiyoshi、Inoue Ituro、Shinomiya Nariyoshi、Matsuo Hirotaka
    • Journal Title

      Molecular Genetics and Metabolism

      Volume: - Issue: 3 Pages: 00126-3

    • DOI

      10.1016/j.ymgme.2022.01.100

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coffee Consumption Reduces Gout Risk Independently of Serum Uric Acid Levels: Mendelian Randomization Analyses Across Ancestry Populations2022

    • Author(s)
      Shirai Yuya、Nakayama Akiyoshi、Kawamura Yusuke、Toyoda Yu、Nakatochi Masahiro、Shimizu Seiko、Shinomiya Nariyoshi、Okada Yukinori、Matsuo Hirotaka、Japan Gout Genomics Consortium (Japan Gout)
    • Journal Title

      ACR Open Rheumatology

      Volume: - Issue: 6 Pages: 534-539

    • DOI

      10.1002/acr2.11425

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] First clinical practice guideline for renal hypouricemia: a rare disorder that aided the development of urate-lowering drugs for gout2021

    • Author(s)
      Nakayama Akiyoshi、Matsuo Hirotaka、Abhishek Abhishek、Ichida Kimiyoshi、Shinomiya Nariyoshi、Guideline Development Committee of Clinical Practice Guideline for Renal Hypouricemia
    • Journal Title

      Rheumatology

      Volume: epub Issue: 9 Pages: 3961-3963

    • DOI

      10.1093/rheumatology/keab322

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Both variants of A1CF and BAZ1B genes are associated with gout susceptibility: a replication study and meta-analysis in a Japanese population2021

    • Author(s)
      Kawaguchi Makoto、Nakayama Akiyoshi、Aoyagi Yuka、Nakamura Takahiro、Shimizu Seiko、Kawamura Yusuke、Takao Mikiya、Tamura Takashi、Hishida Asahi、Nagayoshi Mako、Nagase Mitsuo、Ooyama Keiko、Ooyama Hiroshi、Shinomiya Nariyoshi、Matsuo Hirotaka
    • Journal Title

      Human Cell

      Volume: 34 Issue: 2 Pages: 293-299

    • DOI

      10.1007/s13577-021-00485-4

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A122021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An X chromosome-wide meta-analysis based on Japanese cohorts revealed that non-autosomal variations are associated with serum urate2021

    • Author(s)
      Nakatochi Masahiro、Toyoda Yu、Kanai Masahiro et al. 13th out of 17
    • Journal Title

      Rheumatology

      Volume: - Issue: 9 Pages: 4430-4432

    • DOI

      10.1093/rheumatology/keab404

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic epidemiological analysis of hypouricaemia from 4993 Japanese on non-functional variants of <i>URAT1/SLC22A12</i> gene2021

    • Author(s)
      Nakayama Akiyoshi、Kawamura Yusuke、Toyoda Yu、Shimizu Seiko、Kawaguchi Makoto、Aoki Yuka、Takeuchi Kenji、Okada Rieko、Kubo Yoko、Imakiire Toshihiko、Iwasawa Satoko、Nakashima Hiroshi、Tsunoda Masashi、Ito Keiichi、Kumagai Hiroo、Takada Tappei、Ichida Kimiyoshi、Shinomiya Nariyoshi、Matsuo Hirotaka
    • Journal Title

      Rheumatology

      Volume: 61 Issue: 3 Pages: 1276-1281

    • DOI

      10.1093/rheumatology/keab545

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Proposal for Practical Diagnosis of Renal Hypouricemia: Evidenced from Genetic Studies of Nonfunctional Variants of URAT1/SLC22A12 among 30,685 Japanese Individuals2021

    • Author(s)
      Kawamura Yusuke、Nakayama Akiyoshi、Shimizu Seiko、Toyoda Yu、et al.
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 8 Pages: 1012-1012

    • DOI

      10.3390/biomedicines9081012

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach2021

    • Author(s)
      Ogura Masatsune、Toyoda Yu、Sakiyama Masayuki、Kawamura Yusuke、Nakayama Akiyoshi、et al.
    • Journal Title

      Human Cell

      Volume: 34 Issue: 6 Pages: 1727-1733

    • DOI

      10.1007/s13577-021-00609-w

    • Related Report
      2021 Annual Research Report
    • 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

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] URAT1遺伝子の機能低下型変異による痛風の保護効果は、ABCG2遺伝子の機能低下型変異による痛風のリスク亢進効果を上回る2022

    • Author(s)
      豊田優, 河村優輔, 中山昌喜, 東野俊英, 清水聖子, 大山博司, 市田公美, 四ノ宮成祥, 高田龍平, 松尾洋孝
    • Organizer
      第55回日本痛風・尿酸核酸学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 日本人を対象としたX染色体ワイドメタ解析による尿酸関連SNP rs3020789の同定2022

    • Author(s)
      中杤昌弘, 豊田優, 中山昌喜, 河村優輔, 四ノ宮成祥, 松尾洋孝
    • Organizer
      第55回日本痛風・尿酸核酸学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 日本人コホート集団30,685人を対象とした腎性低尿酸血症の臨床遺伝疫学的解析:実際的診断に向けて2022

    • Author(s)
      河村優輔、中山昌喜、豊田優、西田裕一郎、菱田朝陽、釜野桜子、渋谷謙一、田村高志、中島宏、指宿りえ、上村浩一、原めぐみ、竹内研時、角田正史、有澤幸吉、嶽崎俊郎、田中恵太郎、若井建志、四ノ宮成祥、松尾洋孝
    • Organizer
      第32回日本疫学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 尿中尿酸排泄率と血清尿酸値の特徴的な分布パターンに基づく腎性低尿酸血症の実践的な診断モデルの提案:日本人30685人を対象とした臨床遺伝疫学的解析より2022

    • Author(s)
      河村優輔、中山昌喜、豊田優、川口真、高田雄三、清水聖子、高田龍平、市田公美、四ノ宮成祥、松尾洋孝
    • Organizer
      第55回日本痛風・尿酸核酸学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] APOE ε2ハプロタイプは血清尿酸値を増加させる2022

    • Author(s)
      小倉正恒、豊田優、河村優輔、中山昌喜、高田龍平、清水聖子、東野俊英、中嶌真由子、四ノ宮成祥、松尾洋孝
    • Organizer
      第55回日本痛風・尿酸核酸学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Mendelian randomization analyses revealed that coffee consumption reduces gout risk independently of serum uric acid levels2022

    • Author(s)
      Akiyoshi Nakayama, Yuya Shirai, Yusuke Kawamura, Yu Toyoda, Masahiro Nakatochi, Seiko Shimizu, Nariyoshi Shinomiya, Yukinori Okada, Hirotaka Matsuo
    • Organizer
      European Crystal Network Workshop 2022
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Protective effect of common and rare variants of URAT1/SLC22A12 on gout2021

    • Author(s)
      Yu Toyoda, Yusuke Kawamura, Akiyoshi Nakayama, Hirofumi Nakaoka, Toshihide Higashino, Seiko Shimizu, Hiroshi Ooyama, Keito Morimoto, Naohiro Uchida, Ryuichiro Shigesawa, Kenji Takeuchi, Ituro Inoue, Kimiyoshi Ichida, Hiroshi Suzuki, Nariyoshi Shinomiya, Tappei Takada, and Hirotaka Matsuo
    • Organizer
      The 19th Symposium (PP21) on Purine and Pyrimidine Metabolism in Man
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Substantial gout protective effect by common and rare variants of URAT1/SLC22A12 gene2021

    • Author(s)
      Yu Toyoda, Yusuke Kawamura, Akiyoshi Nakayama, Hirofumi Nakaoka, Toshihide Higashino, Seiko Shimizu, Hiroshi Ooyama, Keito Morimoto, Naohiro Uchida, Ryuichiro Shigesawa, Kenji Takeuchi, Ituro Inoue, Kimiyoshi Ichida, Hiroshi Suzuki, Nariyoshi Shinomiya, Tappei Takada, and Hirotaka Matsuo
    • Organizer
      23th APLAR (Asia-Pacific League of Associations for Rheumatology) Congress
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 日本人を対象としたX染色体ワイドメタ解析による新規尿酸関連SNPの同定2021

    • Author(s)
      中杤昌弘, 豊田優, 金井仁弘, 中山昌喜, 河村優輔, 菱田朝陽, 三上春夫, 松尾恵太郎, 嶽崎俊郎, 桃沢幸秀, The Biobank Japan Project, 鎌谷洋一郎, 市原佐保子, 四ノ宮成祥, 横田充弘, 若井建志, 岡田随象, 松尾洋孝, the Japan Uric Acid Genomics Consortium (Japan Urate)
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 尿酸輸送体遺伝子URAT1/SLC22A12の機能消失型変異に対する日本人集団4,993名における低尿酸血症の遺伝解析2021

    • Author(s)
      中山昌喜、河村優輔、豊田優、清水聖子、川口真、堀江美音、青木優佳、竹内研時、岡田理恵子、久保陽子、今給黎敏彦、岩澤聡子、中島宏、角田正史、伊藤敬一、熊谷裕生、高田龍平、市田公美、四ノ宮成祥、松尾洋孝
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 尿酸輸送体遺伝子URAT1/SLC22A12の機能消失型変異の影響:日本人集団4,993名における低尿酸血症の遺伝子解析2021

    • Author(s)
      中山昌喜, 河村優輔, 豊田優, 清水聖子, 川口真, 鳥羽美帆, 田中里沙, 竹内研時, 岡田理恵子, 久保陽子, 今給黎敏彦, 岩澤聡子, 中島宏, 角田正史, 伊藤敬一, 熊谷裕生, 高田龍平, 市田公美, 四ノ宮成祥, 松尾洋孝
    • Organizer
      第39回日本ヒト細胞学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Proposal of more practical diagnosis of renal hypouricemia: revealed by genetic studies of nonfunctional variants of URAT1/SLC22A12 among 30,685 Japanese individuals.2021

    • Author(s)
      Kawamura Y, Nakayama A, Shimizu S, Toyoda Y, Nakashima H, Takeuchi K, Takada T, Tsunoda M, Arisawa K, Takezaki T, Tanaka K, Ichida K, Wakai K, Shinomiya N and Matsuo H
    • Organizer
      G-CAN 7th Annual Research Symposium
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 病型特異的な痛風関連遺伝子と適応進化の評価:臨床診断された痛風症例のゲノムワイド関連解析から2021

    • Author(s)
      中山昌喜, 中杤昌弘, 河村優輔, 山本健, 中岡博史, 清水聖子, 小山晃英, 栗木清典, 大山博司, 島ノ江千里, 釜野桜子, 前原一輝, 桐原真奈, 嶽崎俊郎, 松尾恵太郎, 鈴木貞夫, 若井建志, 岡田随象, 四ノ宮成祥, 松尾洋孝
    • Organizer
      第31回日本疫学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 痛風・高尿酸血症の分子病態の解明に向けて:ゲノムワイド関連解析(GWAS)等を通じた遺伝統計学的解析2021

    • Author(s)
      松尾洋孝, 高田龍平, 中杤昌弘, 中山昌喜, 大山博司, 長瀬満夫, 日高雄二, 清水徹, 岡田随象, 市田公美, 四ノ宮成祥
    • Organizer
      第54回日本痛風・尿酸核酸学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] ゲノムワイド関連解析による病型特異的な痛風関連遺伝子の同定と日本人の適応進化2021

    • Author(s)
      中山昌喜, 中杤昌弘, 河村優輔, 清水聖子, 清水徹, 大山恵子, 大山博司, 長瀬満夫, 日高雄二, 川口真, 高田龍平, 細谷龍男, 市田公美, 四ノ宮成祥, 松尾洋孝
    • Organizer
      第54回日本痛風・尿酸核酸学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Recent findings in clinico-genetics analyses for clinically-defined gout2021

    • Author(s)
      Matsuo H, Nakatochi M, Nakayama A, Kawamura Y, Toyoda Y, Shimizu S, Takada T, Ichida K, Shinomiya N, Okada Y
    • Organizer
      European Crystal Network
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Clinically-Defined Gout Revealed Multiple Subtype-Specific Gout Loci and Enrichment of Selection Pressure on ABCG2 and ALDH22020

    • Author(s)
      Kawamura Y, Nakayama A, Nakatochi M, Yamamoto K, Nakaoka H, Shimizu S, Maehara K, Kirihara M, Koyama T, Hishida A, Shimizu T, Ooyama H, Nagase M, Shirai Y, Toyoda Y, Takada T, Kamatani Y, Ichida K, Wakai K, Inoue I, Okada Y, Shinomiya N, Matsuo H.
    • Organizer
      22nd Asia Pacific League of Associations for Rheumatology (APLAR 2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Subtype genome-wide meta-analyses of gout: novel gout risk loci and enrichment of selection pressure on ABCG2 and ALDH22020

    • Author(s)
      Kawamura Y, Nakayama A, Nakatochi M, Yamamoto K, Nakaoka H, Shimizu S, Kirihara M, Shimizu T, Ooyama H, Shirai Y, DanjohI, Hosomichi K, Kamatani Y, Kubo M, Ichida K, Wakai K, Inoue I, Okada Y, Shinomiya N, Matsuo H.
    • Organizer
      日本人類遺伝学会第65回大会
    • Related Report
      2020 Research-status Report
  • [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/

    • Related Report
      2021 Annual Research Report

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Published: 2020-09-29   Modified: 2023-01-30  

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