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Systematic Analysis of Pathophysiology of Familial Hypercholesterolemia Due to Different Causal Gene Mutations

Research Project

Project/Area Number 21591160
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKanazawa University

Principal Investigator

KAWASHIRI Masaaki  金沢大学, 附属病院, 講師 (90345637)

Co-Investigator(Kenkyū-buntansha) NOGUCHI Tohru  金沢大学, 医学系・研究科, 助教 (40456421)
Co-Investigator(Renkei-kenkyūsha) IKEWAKI Katsunori  防衛医科大学校, 老年内科, 教授 (40287199)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords脂質代謝異常 / 家族性高コレステロール血症 / 安定同位体 / 常染色体劣性高コレステロール血症 / PCSK9
Research Abstract

The fractional catabolic rate(FCR) of low-density lipoprotein(LDL) apolipoprotein B(apoB) in a patient with autosomal recessive hypercholesterolemia(ARH) was 75% smaller, whereas direct removal of very-LDL apoB was dramatically greater compared with those of normal control subjects. Statin therapy normalized FCR of LDL apoB and increased direct removal of very-LDL in ARH patient. On the other hand, the FCR of patients with homozygous proprotein convertase subtilisin/kexin 9(PCSK9) gene mutation was 52% smaller than that of normal control subjects and normalized by statin therapy. Whereas, both production rate and direct removal of very-LDL was increased compared with those of normal control subjects, which were not changed by statin therapy.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (42 results)

All 2012 2011 2010 2009

All Journal Article (24 results) (of which Peer Reviewed: 23 results) Presentation (16 results) Book (2 results)

  • [Journal Article] Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia : results from stable isotope kinetic study in vivo2012

    • Author(s)
      Tada H, Kawashiri MA, Ikewaki K, Terao Y, Noguchi T, Nakanishi C, Tsuchida M, Takata M, Miwa K, Konno T, Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
    • Journal Title

      Circ Cardiovasc Genet

      Volume: 5 Issue: 1 Pages: 35-41

    • DOI

      10.1161/circgenetics.111.960948

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Novel mutations of cholesteryl ester transfer protein(CETP) gene in Japanese hyperalphalipoproteinemic subjects2012

    • Author(s)
      Ohtani R, Inazu A, Noji Y, Wakasugi T, Miwa K, Tada H, Kawashiri MA, Noguchi T, Nohara A, Kobayashi J, Koizumi J, Yamagishi M, Mabuchi H
    • Journal Title

      Clin Chim Acta

      Volume: 413 Issue: 5-6 Pages: 537-43

    • DOI

      10.1016/j.cca.2011.11.010

    • NAID

      120004026116

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia2012

    • Author(s)
      Kawashiri MA, Nohara A, Noguchi T, Tada H, Nakanishi C, Mori M, Konno T, Hayashi K, Fujino N, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
    • Journal Title

      Am J Cardiol

      Volume: 109 Issue: 3 Pages: 364-9

    • DOI

      10.1016/j.amjcard.2011.09.019

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Impact of out-stent plaque volume on in-stent intimal hyperplasia : Results from serial volumetric analysis with high-gain intravascular ultrasound2012

    • Author(s)
      Tada H, et al., 計10名、2番目
    • Journal Title

      Int J Cardiol

      Volume: (掲載確定) Issue: 2 Pages: 235-239

    • DOI

      10.1016/j.ijcard.2011.01.058

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Insulin secretion and insulin sensitivity on the oral glucose tolerance test (OGTT)in middle-aged Japanese2012

    • Author(s)
      Oka R, et al., 計10名、7番目
    • Journal Title

      Endocr J

      Volume: 59 Pages: 55-64

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel type of familial hypercholesterolemia : double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene2011

    • Author(s)
      Tada H, Kawashiri MA, Ohtani R, Noguchi T, Nakanishi C, Konno T, Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
    • Journal Title

      Atherosclerosis

      Volume: 219 Issue: 2 Pages: 663-6

    • DOI

      10.1016/j.atherosclerosis.2011.08.004

    • NAID

      120003368152

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Impact of bezafibrate and atorvastatin on lipoprotein subclass in patients with type III hyperlipoproteinemia : result from a crossover study2011

    • Author(s)
      Kawashiri MA, Kobayashi J, Nohara A, Noguchi T, Tada H, Nakanishi C, Inazu A, Mabuchi H, Yamagishi M
    • Journal Title

      Clin Chim Acta

      Volume: 412 Issue: 11-12 Pages: 1068-75

    • DOI

      10.1016/j.cca.2011.02.026

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Hokuriku FH Study Group. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan2011

    • Author(s)
      Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Tada H, Nakanishi C, Mori M, Yamagishi M, Inazu A, Koizumi J
    • Journal Title

      Atherosclerosis

      Volume: 214 Issue: 2 Pages: 404-407

    • DOI

      10.1016/j.atherosclerosis.2010.11.005

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus : results from a crossover study2011

    • Author(s)
      Noguchi T, et al., 計14名、9番目
    • Journal Title

      Atherosclerosis

      Volume: 217 Issue: 1 Pages: 165-170

    • DOI

      10.1016/j.atherosclerosis.2011.02.012

    • NAID

      120003141452

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression profiling of the ephrin (EFN)and Eph receptor (EPH) family of genes in atherosclerosis-related human cells2011

    • Author(s)
      Sakamoto A, et la., 計9名、7番目
    • Journal Title

      J Int Med Res

      Volume: 39 Pages: 522-527

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of severe coronary disease associated or not associated with diabetes mellitus on outcome of interventional treatment using stents : results from HERZ (Heart Research Group of Kanazawa) analyses2011

    • Author(s)
      Uchiyama K, et al., 計25名、24番目
    • Journal Title

      J Int Med Res

      Volume: 39 Pages: 549-557

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene and Protein Expression Analysis of Mesenchymal Stem Cells Derived From Rat Adipose Tissue and Bone Marrow2011

    • Author(s)
      Nakanishi C, et al., 計10名、8番目
    • Journal Title

      Circulation Journal

      Volume: 75 Issue: 9 Pages: 2260-2268

    • DOI

      10.1253/circj.CJ-11-0246

    • NAID

      10029340006

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intravascular ultrasound appearance of scattered necrotic core as an index for deterioration of coronary flow during intervention in acute coronary syndrome2011

    • Author(s)
      Sakata K, et al., 計9名、2番目
    • Journal Title

      Hear Vessels

      Volume: (掲載確定) Issue: 5 Pages: 443-452

    • DOI

      10.1007/s00380-011-0175-8

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular genetic epidemiology of homozygous familial hyperchole sterolemia in the Hokuriku district of Japan.2011

    • Author(s)
      Mabuchi H, et al.(計11名、5番目)
    • Journal Title

      Atherosclerosis

      Volume: 214 Pages: 404-407

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of a Novel Missense Mutation in the Sterol 27-Hydroxylase Gene in Two Japanese Patients with Cerebrotendinous Xanthomatosis2010

    • Author(s)
      Nozue T, Higashikata T, Inazu A, Kawashiri MA, Nohara A, Kobayashi J, Koizumi J, Yamagishi M, Mabuchi H
    • Journal Title

      Internal Medicine

      Volume: 49 Issue: 12 Pages: 1127-1131

    • DOI

      10.2169/internalmedicine.49.3277

    • NAID

      130000251640

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation2010

    • Author(s)
      Noguchi T, Katsuda S, Kawashiri MA, Tada H, Nohara A, Inazu A, Yamagishi M, Kobayashi J, Mabuchi H
    • Journal Title

      Atherosclerosis

      Volume: 210 Issue: 1 Pages: 166-72

    • DOI

      10.1016/j.atherosclerosis.2009.11.018

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] The E32K variant of PCSK9 exacerbates the phenotype of familial hype rcholesterolaemia by increasing PCSK9 function and concentration in the circulation.2010

    • Author(s)
      Noguchi T, et al.(計9名、3番目)
    • Journal Title

      Atherosclerosis.

      Volume: 210 Pages: 166-172

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impacts of visceral adipose tissue and subcutaneous adipose tissue on metabolic risk factors in middle-aged Japanese.2010

    • Author(s)
      Oka R, et al.(計17名、14番目)
    • Journal Title

      Obesity

      Volume: 18 Pages: 153-160

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients2009

    • Author(s)
      Miwa K, Inazu A, Kawashiri MA, Nohara A, Higashikata T, Kobayashi J, Koizumi J, Nakajima K, Nakano T, Niimi M, Mabuchi H, Yamagishi M
    • Journal Title

      Clin ChimActa

      Volume: 402 Issue: 1-2 Pages: 19-24

    • DOI

      10.1016/j.cca.2008.12.012

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Formation of prebeta1-HDL during lipolysis of triglyceride-rich lipoprotein2009

    • Author(s)
      Miyazaki O, Fukamachi I, Mori A, Hashimoto H, Kawashiri MA, Nohara A, Noguchi T, Inazu A, Yamagishi M, Mabuchi H, Kobayashi J
    • Journal Title

      BiochemBiophys Res Commun

      Volume: 379 Issue: 1 Pages: 55-9

    • DOI

      10.1016/j.bbrc.2008.11.146

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients2009

    • Author(s)
      Miwa K, Kawashiri M (計12名、3番目)
    • Journal Title

      Clin Chim Acta. 402

      Pages: 19-24

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Apolipoprotein B gene mutations and fatty liver in Japanese hypobetali poproteinemia2009

    • Author(s)
      Katsuda S, Kawashiri M (計13名、2番目)
    • Journal Title

      Clin Chim Acta. 399

      Pages: 64-68

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel method for determining functional LDL receptor activity in familial hypercholesterolemia : application of the CD3/CD28 assay in lymphocytes2009

    • Author(s)
      Tada H, Kawashiri M (計12名、2番目)
    • Journal Title

      Clin Chim Acta. 400

      Pages: 42-47

    • NAID

      120001063575

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article]2009

    • Author(s)
      川尻剛照, 多田隼人, 山岸正和
    • Journal Title

      炎症・再生医学事典 (共著) 虚血性心疾患・動脈硬化(朝倉書店)

      Pages: 251-255

    • Related Report
      2009 Annual Research Report
  • [Presentation] et al. Impact of impaired LDL catabolism and increased VLDL and VLDL remnant production on hypercholesterolemia in homozygous PCSK9 mutation : Evidence from a kinetic study with stable isotope2011

    • Author(s)
      Masaaki Kawashiri, Katsunori Ikewaki, Tohru Noguchi
    • Organizer
      84^<th> American Heart Association 2011 Scientific Sessions
    • Place of Presentation
      Orange County Convention Center, Orlando, USA
    • Related Report
      2011 Final Research Report
  • [Presentation] パネルディスカッション多剤併用による積極的脂質管理と新規脂質低下剤の可能性2011

    • Author(s)
      川尻剛照
    • Organizer
      第59回日本心臓病学会学術集会
    • Place of Presentation
      神戸国際会議場(神戸、兵庫県)
    • Related Report
      2011 Final Research Report
  • [Presentation] Impact of elevated PCSK9 levels on regulation of LDL-cholesterol after statin treatment : Study with different types of lipid lowering drugs2011

    • Author(s)
      川尻剛照,野口徹, ほか
    • Organizer
      第75回日本循環器学会総会・学術集会
    • Place of Presentation
      パシフィコ横浜(横浜、神奈川県)
    • Related Report
      2011 Final Research Report
  • [Presentation] Impaired LDL catabolism and increased VLDL and VLDL remnant production in homozygous familial hypercholesterolemia with PCSK9 gene mutation2011

    • Author(s)
      川尻剛照,池脇克則,野口徹, ほか
    • Organizer
      第75回日本循環器学会総会・学術集会
    • Place of Presentation
      パシフィコ横浜(横浜、神奈川県)
    • Related Report
      2011 Final Research Report
  • [Presentation] Impact of elevated PCSK9 levels on regulation of LDL-cholesterol after statin treatment : Study with different typesof lipid lowering drugs2011

    • Author(s)
      Masaaki Kawashiri, Katsunori Ikewaki, Tohru Noguchi, et al
    • Organizer
      60^<th> Annual Scientific Session of American College of Cardiology
    • Place of Presentation
      Ernest N. Morial Convention Center, New Orleans,(USA)
    • Related Report
      2011 Final Research Report
  • [Presentation] Impact of elevated PCSK9 legels on regulation of LDL-cholesterol after statin treatment : Study with different types of lipid lowering drugs2011

    • Author(s)
      Kawashiri M, et al., 計8名、1番目
    • Organizer
      60^<th> Annual Scientific Session of American College of Cardiology
    • Place of Presentation
      Ernest N. Morial Conventi on Center (アメリカ)
    • Related Report
      2011 Annual Research Report
  • [Presentation] Impact of impared LDL catabolism and increased VLDL and VLDL remnant production on hypercholesterolemia in homozygous PCSK9 gene mutation : Evidence from kinetic study with stable isotope2011

    • Author(s)
      Kawashiri M, et al., 計9名、1番目
    • Organizer
      American Heart Association Scientific Sessions 2011
    • Place of Presentation
      Orange County Convention Center(アメリカ)
    • Related Report
      2011 Annual Research Report
  • [Presentation] パネルディスカッション多剤併用による積極的脂質管理と新規脂質低下剤の可能性2011

    • Author(s)
      川尻剛照、野原淳、馬渕宏、山岸正和
    • Organizer
      第59回日本心臓病学会学術集会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Related Report
      2011 Annual Research Report
  • [Presentation] 脂質異常症とLDLアフェレシス「FHヘテロ接合体とLDLアフェレシス」2010

    • Author(s)
      川尻剛照
    • Organizer
      第31回日本アフェレシス学会学術大会
    • Place of Presentation
      ディズニーアンバサダーホテル(千葉県)(招待講演)
    • Year and Date
      2010-11-05
    • Related Report
      2010 Annual Research Report
  • [Presentation] Impact of the LDL-receptor-related molecules on the achievement of optimal LDL cholesterol level : Evidence from newly identified gene mutations2010

    • Author(s)
      川尻剛照, 多田隼人, 中西千明, 山岸正和, 野口徹, 野原淳, 小林淳二, 馬渕宏, 池脇克則
    • Organizer
      第74回日本循環器学会総会・学術集会シンポジウム
    • Place of Presentation
      グランドプリンスホテル京都 (京都府)
    • Year and Date
      2010-03-05
    • Related Report
      2009 Annual Research Report
  • [Presentation] Elevation of PCSK9 levels after statin therapy : study with different types of lipid lowering drugs2010

    • Author(s)
      川尻剛照,野口徹, ほか
    • Organizer
      第43回日本動脈硬化学会総会・学術集会
    • Place of Presentation
      ロイトン札幌(札幌、北海道)
    • Related Report
      2011 Final Research Report
  • [Presentation] ワークショップFHヘテロ接合体とLDLアフェレーシス2010

    • Author(s)
      川尻剛照
    • Organizer
      第31回日本アフェレシス学会学術大会
    • Place of Presentation
      ディズニーアンバサダーホテル(幕張、千葉県)
    • Related Report
      2011 Final Research Report
  • [Presentation] The effects of combination therapy with permitted maximum doses of rosuvastatin, ezetimibe and colestimide in patients with heterozygous familial hypercholesterolemia2010

    • Author(s)
      川尻剛照
    • Organizer
      第75回日本循環器学会総会・学術集会
    • Place of Presentation
      長良川国際会議場(岐阜、岐阜県)
    • Related Report
      2011 Final Research Report
  • [Presentation] シンポジウムImpact of the LDL-receptor-related molecules on achievement of optimal LDL cholesterol level : evidence from newly identified gene mutations2010

    • Author(s)
      川尻剛照
    • Organizer
      第74回日本循環器学会総会・学術集会
    • Place of Presentation
      国立京都国際会館(京都、京都府)
    • Related Report
      2011 Final Research Report
  • [Presentation] Enhanced effect of bezafibrate on HDL subfraction in patients with dysbetalipoproteinemia : Results from a crossover study with atorvastatin2009

    • Author(s)
      Masaaki Kawashiri
    • Organizer
      2009 International Symposium on Atherosclerosis
    • Place of Presentation
      Hynes Convention Center, Boston, USA
    • Related Report
      2011 Final Research Report
  • [Presentation] Impact of co-administration of atorvastatin annd bezafibrate on the lipoprotein subclass : Comparison between apoE2/2 and E3/32009

    • Author(s)
      Masaaki Kawashiri
    • Organizer
      17^<th> Asian Pacific Congress of Cardiology
    • Place of Presentation
      International Conference Center(Kyoto)
    • Related Report
      2011 Final Research Report
  • [Book] 成功に導くPCI治療戦略低HDL-Cは改善すべきか2012

    • Author(s)
      川尻剛照
    • Publisher
      南江堂
    • Related Report
      2011 Annual Research Report
  • [Book] 分子予防環境医学(共著) 動脈硬化症2010

    • Author(s)
      川尻剛照、山岸正和
    • Total Pages
      13
    • Publisher
      本の泉社
    • Related Report
      2010 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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