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Elucidation of the effect of variants in the PCSK9 gene and molecular type on lifestyle-related diseases and its regulatory mechanism

Research Project

Project/Area Number 17K08681
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

Hori Mika  国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60598043)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords家族性高コレステロール血症 / 冠動脈疾患 / 糖尿病 / PCSK9 / LDLR / バリアント / 遺伝子解析 / 遺伝子変異 / 脂質異常症 / 変異 / 肝細胞 / iPS細胞 / 分子型 / 生活習慣病
Outline of Final Research Achievements

The variants in the PCSK9 gene detected in Japan were annotated in familial hypercholesterolemia (FH) according to ACMG guideline. The E32K variant in the PCSK9 gene can cause FH, but the V4I variant alone does not contribute to the pathophysiology of FH. The V4I・E32K variants in the PCSK9 gene showed no difference in the levels of intracellular expression and secretion of PCSK9, intracellular and membrane expression of LDLR and LDL uptake compared to wild type of PCSK9 using cultured cells. In addition, the prevalence of diabetes mellitus was lower in patients with variants in the LDLR and PCSK9 genes than in patients without variants in the LDLR and PCSK9 genes. Patients with FH with variants in the LDLR gene and V4I/E32K variant in the PCSK9 gene had poor prognosis compared to patients with a variant in the LDLR or PCSK9 gene.

Academic Significance and Societal Importance of the Research Achievements

本邦のFH 遺伝子解析ではPCSK9 遺伝子V4I・E32Kバリアントが高頻度に検出される。これらのバリアントの意義付けはFH 遺伝子解析結果の解釈に役立つ。また、PCSK9遺伝子 V4I/E32KバリアントにLDLR 遺伝子バリアントの重なるFH患者は予後不良であることから、FH 遺伝子解析により冠動脈疾患高リスク患者を早期に発見し、早期診断・早期の治療開始が重要である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (23 results)

All 2020 2019 2018 2017

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 2 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Book (1 results)

  • [Journal Article] The benign c.344G>A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia.2020

    • Author(s)
      Hori M*(corresponding author), Takahashi A, Son C, Ogura M, Harada-Shiba M*
    • Journal Title

      Lipids in Health and Disease

      Volume: - Issue: 1 Pages: 62-62

    • DOI

      10.1186/s12944-020-01252-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Catalog of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia2020

    • Author(s)
      Tada H*, Hori M*(*equal contribution), Nomura A, Hosomichi K, Nohara A, Kawashiri M*, Harada-Shiba M*
    • Journal Title

      Journal of Clinical Lipidology

      Volume: - Issue: 3 Pages: 346-351

    • DOI

      10.1016/j.jacl.2020.03.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmaceutical Research for Inherited Metabolic Disorders of the Liver Using Human Induced Pluripotent Stem Cell and Genome Editing Technologies2019

    • Author(s)
      Yamashita T, Takayama K, Hori M, Harada-Shiba M, Mizuguchi H.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 3 Pages: 312-318

    • DOI

      10.1248/bpb.b18-00544

    • NAID

      130007607360

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-03-01
    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients2019

    • Author(s)
      Hori Mika、Ohta Naotaka、Takahashi Atsushi、Masuda Hiroaki、Isoda Rieko、Yamamoto Suguru、Son Cheol、Ogura Masatsune、Hosoda Kiminori、Miyamoto Yoshihiro、Harada-Shiba Mariko
    • Journal Title

      Atherosclerosis

      Volume: 289 Pages: 101-108

    • DOI

      10.1016/j.atherosclerosis.2019.08.004

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice.2019

    • Author(s)
      Takafuji Y, Hori M , Mizuno T, Harada-Shiba M
    • Journal Title

      Cardiovascular Research

      Volume: 115 Issue: 6 Pages: 1041-1051

    • DOI

      10.1093/cvr/cvy271

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Detection of the benign c.2579C>T (p.A860V) variant of the LDLR gene in a pedigree-based genetic analysis of familial hypercholesterolemia.2019

    • Author(s)
      Hori M, Miyauchi E, Son C, Harada-Shiba M
    • Journal Title

      Jounral of Clinical Lipidology

      Volume: 13 Issue: 2 Pages: 335-339

    • DOI

      10.1016/j.jacl.2019.01.004

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Discontinuation of LDL apheresis with evolocumab in an FH patient with a duplication of exon 2-6 in the LDLR gene.2019

    • Author(s)
      Nose D, Hori M, Miyamoto Y, Imaizumi S, Harada-Shiba M, Saku K, Miura S
    • Journal Title

      Journal of Cardiology Cases.

      Volume: 19 Issue: 2 Pages: 55-58

    • DOI

      10.1016/j.jccase.2018.10.005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Coronary Artery Plaque Regression by a PCSK9 Antibody and Rosuvastatin in Double-heterozygous Familial Hypercholesterolemia with an <i>LDL Receptor</i> Mutation and a <i>PCSK9</i> V4I Mutation2018

    • Author(s)
      Shirahama Ryo、Ono Takamichi、Nagamatsu Suguru、Sueta Daisuke、Takashio Seiji、Chitose Tadasuke、Fujisue Koichiro、Sakamoto Kenji、Yamamoto Eiichiro、Izumiya Yasuhiro、Kaikita Koichi、Hokimoto Seiji、Hori Mika、Harada-Shiba Mariko、Kajiwara Ichiro、Ogawa Hisao、Tsujita Kenichi
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 24 Pages: 3551-3557

    • DOI

      10.2169/internalmedicine.1060-18

    • NAID

      130007531213

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans2018

    • Author(s)
      Takahashi Mami、Hori Mika、Ishigamori Rikako、Mutoh Michihiro、Imai Toshio、Nakagama Hitoshi
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 10 Pages: 3013-3023

    • DOI

      10.1111/cas.13766

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucagon-like peptide-1 receptor agonists reduced the LDL-cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins.2018

    • Author(s)
      Hasegawa Y, Hori M* (corresponding author), Nakagami T, Harada-Shiba M*, Uchigata Y
    • Journal Title

      Jounral of Clinical Lipidology

      Volume: 12 Issue: 1 Pages: 62-69

    • DOI

      10.1016/j.jacl.2017.11.006

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] A case of coronary artery plaque regression by a PCSK9 antibody and rosuvastatin in double-heterozygous familial hypercholesterolemia with an LDLR mutation and a PCSK9 V4I mutation.2018

    • Author(s)
      1.Shirahama R, Ono T, Nagamatsu S, Sueta D, Takashio S, Chitose T, Fujisue K, Sakamoto K, Yamamoto E, Izumiya Y, Kaikita K, Hokimoto S, Hori M, Harada-Shiba M, Kajiwara I, Ogawa H, Tsujita K.
    • Journal Title

      Internal Medicine

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Achilles Tendon Ultrasonography for Diagnosis of Familial Hypercholesterolemia Among Japanese Subjects2017

    • Author(s)
      Michikura M, Ogura M, Yamamoto M, Sekimoto M, Fuke C, Hori M, Arai K, Kihara S, Hosoda K, Yanagi K, Harada-Shiba M
    • Journal Title

      Circulation Journal

      Volume: 81 Issue: 12 Pages: 1879-1885

    • DOI

      10.1253/circj.CJ-17-0041

    • NAID

      130006219114

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 家族性高コレステロール血症の遺伝子解析とその有用性2019

    • Author(s)
      堀美香、斯波真理子
    • Organizer
      第67回日本心臓病学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Role of PCSK9 as a modifier in familial hypercholesterolemia.2018

    • Author(s)
      Hori M, Harada-Shiba M.
    • Organizer
      第50回日本動脈硬化学会総会・学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Prevalence, Clinical Characteristics and Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia Patients with Double-heterozygous Mutation of LDLR and PCSK9 Gain-of-function Mutation.2018

    • Author(s)
      Doi T, Hori M, Harada-Shiba M, Kataoka Y, Nishikawa R, Tsuda K, Nishimura K, Ogura M, Noguchi T, Yasuda S.
    • Organizer
      American Heart Association
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The Frequency and the Spectrum of Causative Mutations in Japanese Familial Hypercholesterolemia Heterozygotes2018

    • Author(s)
      Hori M, Ohta N, Masuda H, Son C, Hosoda K, Ogura M, Miyamoto Y, Harada-Shiba M
    • Organizer
      86th EAS Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] FHホモ接合体におけるコレステロール引き抜き能2018

    • Author(s)
      小倉正恒, 堀美香, 斯波真理子
    • Organizer
      第50回日本動脈硬化学会総会・学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 家族性高コレステロール血症ヘテロ接合体における遺伝子診断とLDLR/PCSK9遺伝子変異の分布2018

    • Author(s)
      堀美香, 太田直孝, 増田弘明, 磯田理恵子, 孫徹, 小倉正恒, 細田公則, 宮本恵宏, 斯波真理子
    • Organizer
      第55回日本臨床分子医学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Role of PCSK9 as a modifier in familial hypercholesterolemia2018

    • Author(s)
      堀 美香、斯波 真理子
    • Organizer
      第50回日本動脈硬化学会総会・学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 家族性高コレステロール血症ヘテロ接合体における遺伝子診断と LDLR/PCSK9遺伝子変異の分布2018

    • Author(s)
      堀 美香、太田 直孝、増田 弘明、磯田 理恵子、孫 徹、小倉  正恒、細田 公則、宮本 恵宏、斯波 真理子
    • Organizer
      第55回日本臨床分子医学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] The frequency and the spectrum of causative mutations in Japanese familial hypercholesterolemia heterozygotes2018

    • Author(s)
      Hori M, Ohta N, Masuda H, Son C, Hosoda K, Ogura M, Miyamoto Y, Harada-Shiba M
    • Organizer
      86th European Atherosclrosis Society Congress
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] The frequency and the spectrum of FH causing mutations in Japanese heterozygous familial hypercholesterolemia2017

    • Author(s)
      Hori M, Ohta N, Masuda H, Ogura M, Makino H, Tamanaha T, Miyamoto Y, Harada-Shiba M
    • Organizer
      第49回日本動脈硬化学会総会・学術集会
    • Related Report
      2017 Research-status Report
  • [Book] The Lipid2018

    • Author(s)
      太田直孝、堀美香、宮本恵宏、斯波真理子
    • Total Pages
      6
    • Publisher
      メディカルレビュー社
    • ISBN
      9784779220258
    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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