Discovery and mechanistic analysis of a novel molecule associated with high-density lipoprotein metabolism using whole exome sequencing

2018 Fiscal Year Annual Research Report

• Project/Area Number: 15K09118
• Research Institution: Kanazawa University
• Principal Investigator: 川尻 剛照 金沢大学, 医学系, 准教授 (90345637)
• Co-Investigator(Kenkyū-buntansha): 野原 淳 金沢大学, 保健管理センター, 助教 (50313648) ; 多田 隼人 金沢大学, 附属病院, 助教 (90623653)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 高比重リポ蛋白 / 動脈硬化 / 全エクソームシーケンス

Outline of Annual Research Achievements

動脈硬化症予防を目的に、症例に立脚した高比重リポ蛋白（HDL）代謝異常症の病態解明を目指した研究を引き続き行った。発端者は①著明な高HDLコレステロール血症（170mg/dL）と②著明な低HDLコレステロール血症2例である。
まず、②低HDLコレステロール血症2例（症例１：28歳女性、HDLコレステロール値2mg/dL、症例２：35歳女性、同6mg/dL）とその家族を全エクソームシーケンス法で解析した。症例１はABCA1遺伝子c.6230C>A/c.6137G>Aのコンパウンドヘテロ接合体、症例２もABCA1遺伝子c.2842G>A/c.1130C>Tのコンパウンドヘテロ接合体と診断された。いずれも既知の遺伝子異常によることが判明したため、機能解析は見送った。
次に、①著明な高HDLコレステロール血症の原因「分子X」遺伝子の機能解析に取り組んだ。HEK293細胞へ遺伝子導入を行い、遺伝子発現を確認した。HEK293細胞をアイソトープラベルしたコレステロールと24時間共培養し、さらにアポA-Iを添加し24時間共培養し、コレステロール引き抜き能の検討を試みた。コントロールと比較し、「分子X」遺伝子導入細胞のコレステロール引き抜き能に有意差を認めなかった。この結果は、症例①の高HDLコレステロール血症が「分子X」のコレステロール引き抜き能亢進によらない可能性を示唆する。しかしながら、本研究はin vitroの検討であり、生体内の状況を必ずしも反映していない可能性があり、更なる検証が必要である。

Research Products

• [Journal Article] Functional analysis of KCNH2 gene mutations of type 2 long QT syndrome in larval zebrafish using microscopy and electrocardiography. (2019)
  • Author(s): Tanaka Y, Hayashi K, Fujino N, Konno T, Tada H, Nakanishi C, Hodatsu A, Tsuda T, Nagata Y, Teramoto R, Yoshida S, Nomura A, Kawashiri MA, Yamagishi M.
  • Journal Title: Heart Vessels. Volume: 34 Pages: 159-166
  • DOI: 10.1007/s00380-018-1231-4.
  • Peer Reviewed
• [Journal Article] Genetic Variations, Triglycerides, and Atherosclerotic Disease. (2019)
  • Author(s): Tada H, Kawashiri MA.
  • Journal Title: J Atheroscler Thromb. Volume: 26 Pages: 128-131
  • DOI: 10.5551/jat.ED102.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical whole exome sequencing in severe hypertriglyceridemia. (2019)
  • Author(s): Tada H, Nomura A, Okada H, Nakahashi T, Nozue T, Hayashi K, Nohara A, Yagi K, Inazu A, Michishita I, Mabuchi H, Yamagishi M, Kawashiri MA.
  • Journal Title: Clin Chim Acta. Volume: 488 Pages: 31-39
  • DOI: 10.1016/j.cca.2018.10.041.
  • Peer Reviewed
• [Journal Article] Function and Immunogenicity of Gene-corrected iPSC-derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia. (2019)
  • Author(s): Okada H, Nakanishi C, Yoshida S, Shimojima M, Yokawa J, Mori M, Tada H, Yoshimuta T, Hayashi K, Yamano T, Hanayama R, Yamagishi M, Kawashiri MA.
  • Journal Title: Sci Rep. Volume: 9 Pages: 4695
  • DOI: 10.1038/s41598-019-41056-w.
  • Peer Reviewed
• [Journal Article] Impact of B-Type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients With Nonvalvular Atrial Fibrillation - The Hokuriku-Plus AF Registry. (2018)
  • Author(s): Hayashi K, Tsuda T, Nomura A, Fujino N, Nohara A, Sakata K, Konno T, Nakanishi C, Tada H, Nagata Y, Teramoto R, Tanaka Y, Kawashiri MA, Yamagishi M; Hokuriku-Plus AF Registry Investigators.
  • Journal Title: Circ J. Volume: 82 Pages: 1271-1278
  • DOI: 10.1253/circj.CJ-17-1085.
  • Peer Reviewed / Open Access
• [Journal Article] Impact of stent deformity induced by the kissing balloon technique for bifurcating lesions on in-stent restenosis after coronary intervention. (2018)
  • Author(s): Gamou T, Sakata K, Terai H, Horita Y, Ikeda M, Namura M, Yamagishi M, Kawashiri MA.
  • Journal Title: J Interv Cardiol. Volume: 31 Pages: 421-429
  • DOI: 10.1111/joic.12504.
  • Peer Reviewed
• [Journal Article] Remnant-like particles and coronary artery disease in familial hypercholesterolemia. (2018)
  • Author(s): Tada H, Kawashiri MA, Nohara A, Sakata K, Inazu A, Mabuchi H, Yamagishi M, Hayashi K.
  • Journal Title: Clin Chim Acta. Volume: 482 Pages: 120-123
  • DOI: 10.1016/j.cca.2018.04.007.
  • Peer Reviewed
• [Journal Article] Amiodarone-induced reversible and irreversible hepatotoxicity: two case reports. (2018)
  • Author(s): Tsuda T, Tada H, Tanaka Y, Nishida N, Yoshida T, Sawada T, Sakata K, Hayashi K, Kawashiri MA, Oyama T, Sasaki M, Kurose N, Yamagishi M.
  • Journal Title: J Med Case Rep. Volume: 12 Pages: 95
  • DOI: 10.1186/s13256-018-1629-8.
  • Peer Reviewed
• [Journal Article] Additive Prognostic Value of Carotid Plaque Score to Enhance the Age, Creatinine, and Ejection Fraction Score in Patients with Acute Coronary Syndrome. (2018)
  • Author(s): Nakahashi T, Tada H, Sakata K, Nomura A, Ohira M, Mori M, Takamura M, Hayashi K, Yamagishi M, Kawashiri MA.
  • Journal Title: J Atheroscler Thromb. Volume: 25 Pages: 709-719
  • DOI: 10.5551/jat.42317.
  • Peer Reviewed
• [Journal Article] Oral Fat Tolerance Test for Sitosterolemia and Familial Hypercholesterolemia: A Study Protocol. (2018)
  • Author(s): Nomura A, Tada H, Nohara A, Kawashiri MA, Yamagishi M.
  • Journal Title: J Atheroscler Thromb. Volume: 25 Pages: 741-746
  • DOI: 10.5551/jat.42960.
  • Peer Reviewed / Open Access
• [Journal Article] Aortic Root Calcification Score as an Independent Factor for Predicting Major Adverse Cardiac Events in Familial Hypercholesterolemia. (2018)
  • Author(s): Okada H, Tada H, Hayashi K, Kawashima H, Takata T, Sakata K, Nohara A, Mabuchi H, Yamagishi M, Kawashiri MA.
  • Journal Title: J Atheroscler Thromb. Volume: 25 Pages: 634-642
  • DOI: 10.5551/jat.42705.
  • Peer Reviewed / Open Access
• [Journal Article] Paradoxical impact of decreased low-density lipoprotein cholesterol level at baseline on the long-term prognosis in patients with acute coronary syndrome. (2018)
  • Author(s): Nakahashi T, Tada H, Sakata K, Yakuta Y, Tanaka Y, Nomura A, Gamou T, Terai H, Horita Y, Ikeda M, Namura M, Takamura M, Hayashi K, Yamagishi M, Kawashiri MA.
  • Journal Title: Heart Vessels. Volume: 33 Pages: 695-705
  • DOI: 10.1007/s00380-017-1111-3.
  • Peer Reviewed / Open Access
• [Journal Article] Prominent Tendon Xanthomas and Abdominal Aortic Aneurysm Associated with Cerebrotendinous Xanthomatosis Identified Using Whole Exome Sequencing. (2018)
  • Author(s): Tada H, Inaba S, Pozharitckaia D, Kawashiri MA.
  • Journal Title: Intern Med. Volume: 57 Pages: 1119-1122
  • DOI: 10.2169/internalmedicine.9687-17.
  • Peer Reviewed
• [Journal Article] Clinical characteristics of spontaneous isolated visceral artery dissection. (2018)
  • Author(s): Tanaka Y, Yoshimuta T, Kimura K, Iino K, Tamura Y, Sakata K, Hayashi K, Takemura H, Yamagishi M, Kawashiri MA.
  • Journal Title: J Vasc Surg. Volume: 67 Pages: 1127-1133
  • DOI: 10.1016/j.jvs.2017.08.054.
  • Peer Reviewed
• [Journal Article] Huge Metastatic Gastrointestinal Stromal Tumor Occupying the Right Ventricle. (2018)
  • Author(s): Tamura Y, Tada H, Kato H, Iino K, Hayashi K, Kawashiri MA, Takemura H, Yamagishi M.
  • Journal Title: Circ J. Volume: 82 Pages: 1469-1470
  • DOI: 10.1253/circj.CJ-17-0722.
  • Peer Reviewed / Open Access
• [Journal Article] Author Correction: Heart Failure Phenotypes Induced by Knockdown of DAPIT in Zebrafish: A New Insight into Mechanism of Dilated Cardiomyopathy. (2018)
  • Author(s): Nagata Y, Yamagishi M, Konno T, Nakanishi C, Asano Y, Ito S, Nakajima Y, Seguchi O, Fujino N, Kawashiri MA, Takashima S, Kitakaze M, Hayashi K.
  • Journal Title: Sci Rep. Volume: 8 Pages: 7768
  • DOI: 10.1038/s41598-018-26012-4.
  • Peer Reviewed
• [Journal Article] Mendelian randomization: Its impact on cardiovascular disease. (2018)
  • Author(s): Kawashiri MA, Tada H, Nomura A, Yamagishi M.
  • Journal Title: J Cardiol. Volume: 72 Pages: 307-313
  • DOI: 10.1016/j.jjcc.2018.04.007.
  • Peer Reviewed / Open Access
• [Journal Article] Very late bare metal stent thrombosis in the setting of discontinuation of optimal medical therapy for 2 years. (2018)
  • Author(s): Murai K, Sakata K, Mabuchi T, Yamaguchi M, Mori M, Hayashi K, Kawashiri MA.
  • Journal Title: Cardiovasc Diagn Ther. Volume: 8 Pages: 186-189
  • DOI: 10.21037/cdt.2018.03.09.
  • Peer Reviewed
• [Journal Article] Multi-vessel Coronary Vasospasm after Beta-blocker Administration. (2018)
  • Author(s): Tamura Y, Sakata K, Kawashiri MA, Yamagishi M.
  • Journal Title: Intern Med. Volume: 57 Pages: 3219-3220
  • DOI: 10.2169/internalmedicine.1165-18.
  • Peer Reviewed
• [Journal Article] Effects of prehospital epinephrine administration on neurologically intact survival in bystander-witnessed out-of-hospital cardiac arrest patients with non-shockable rhythm depend on prehospital cardiopulmonary resuscitation duration required to hospital arrival. (2018)
  • Author(s): Funada A, Goto Y, Tada H, Shimojima M, Hayashi K, Kawashiri MA, Yamagishi M.
  • Journal Title: Heart Vessels. Volume: 33 Pages: 1525-1533
  • DOI: 10.1007/s00380-018-1205-6.
  • Peer Reviewed / Open Access
• [Journal Article] Post-prandial Remnant Lipoprotein Metabolism in Sitosterolemia. (2018)
  • Author(s): Tada H, Nomura A, Nohara A, Inazu A, Mabuchi H, Yamagishi M, Kawashiri MA.
  • Journal Title: J Atheroscler Thromb. Volume: 25 Pages: 1188-1195
  • DOI: 10.5551/jat.44768.
  • Peer Reviewed / Open Access
• [Journal Article] First case of sitosterolemia caused by double heterozygous mutations in ABCG5 and ABCG8 genes. (2018)
  • Author(s): Tada H, Nomura A, Yamagishi M, Kawashiri MA.
  • Journal Title: J Clin Lipidol. Volume: 12 Pages: 1164-1168
  • DOI: 10.1016/j.jacl.2018.06.003.
  • Peer Reviewed
• [Journal Article] Sitosterolemia, Hypercholesterolemia, and Coronary Artery Disease. (2018)
  • Author(s): Tada H, Nohara A, Inazu A, Sakuma N, Mabuchi H, Kawashiri MA.
  • Journal Title: J Atheroscler Thromb. Volume: 25 Pages: 783-789
  • DOI: 10.5551/jat.RV17024.
  • Peer Reviewed / Open Access
• [Journal Article] Serum triglycerides predict first cardiovascular events in diabetic patients with hypercholesterolemia and retinopathy. (2018)
  • Author(s): Tada H, Kawashiri MA, Nomura A, Yoshimura K, Itoh H, Komuro I, Yamagishi M.
  • Journal Title: Eur J Prev Cardiol. Volume: 25 Pages: 1852-1860
  • DOI: 10.1177/2047487318796989.
  • Peer Reviewed
• [Journal Article] Spontaneous Isolated Superior Mesenteric Artery Dissection Requiring Emergent Surgery. (2018)
  • Author(s): Tanaka Y, Tada H, Takeda Y, Iino K, Hayashi K, Takemura H, Yamagishi M, Kawashiri MA.
  • Journal Title: Intern Med. Volume: 57 Pages: 2681-2684
  • DOI: 10.2169/internalmedicine.0641-17.
  • Peer Reviewed / Open Access
• [Journal Article] Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease. (2018)
  • Author(s): Tada H, Kawashiri MA, Nomura A, Teramoto R, Hosomichi K, Nohara A, Inazu A, Mabuchi H, Tajima A, Yamagishi M.
  • Journal Title: J Clin Lipidol. Volume: 12 Pages: 1436-1444
  • DOI: 10.1016/j.jacl.2018.08.006.
  • Peer Reviewed
• [Journal Article] Limited effects of long-term enzyme replacement therapy on the cardiac conduction system in Fabry disease. (2018)
  • Author(s): Kaneda T, Takeda M, Suematsu T, Yamamoto R, Takata M, Higashikata T, Ino H, Tsujibata A, Hayashi K, Fujino N, Kawashiri MA.
  • Journal Title: J Cardiol Cases. Volume: 17 Pages: 178-181
  • DOI: 10.1016/j.jccase.2018.01.004.
  • Peer Reviewed
• [Journal Article] Severe Mitral Regurgitation As a Result of Rupture of Mitral Valve Chordae Tendineae in a Patient With Graves Disease. (2018)
  • Author(s): Karashima S, Tsuda T, Kometani M, Oka R, Demura M, Kawashiri MA, Takeda Y, Hayashi K, Yoneda T.
  • Journal Title: J Endocr Soc. Volume: 2 Pages: 1246-1250
  • DOI: 10.1210/js.2018-00173.
  • Peer Reviewed
• [Journal Article] Associations between questionnaires on lifestyle and atherosclerotic cardiovascular disease in a Japanese general population: A cross-sectional study. (2018)
  • Author(s): Tada H, Kawashiri MA, Yasuda K, Yamagishi M.
  • Journal Title: PLoS One. Volume: 13 Pages: e0208135
  • DOI: 10.1371/journal.pone.0208135.
  • Peer Reviewed
• [Journal Article] Impact of genetic testing on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia (GenTLe-FH): a randomised waiting list controlled open-label study protocol. (2018)
  • Author(s): Nomura A, Tada H, Okada H, Nohara A, Ishikawa H, Yoshimura K, Kawashiri MA.
  • Journal Title: BMJ Open. Volume: 8 Pages: e023636
  • DOI: 10.1136/bmjopen-2018-023636.
  • Peer Reviewed
• [Presentation] Familial Hypercholesterolemia (2018)
  • Author(s): Kawashiri M
  • Organizer: 23nd Annual Scientific Meeting of the Internal Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research / Invited
• [Presentation] PCSK9を標的にした新たな冠動脈疾患治療薬の誕生：疫学研究からの新薬開発 (2018)
  • Author(s): 川尻剛照
  • Organizer: 日本慢性疾患重症化予防学会 第4回年次学術集会
  • Invited
• [Presentation] 重症家族性高コレステロール血症の治療選択におけるLp(a)の意義 (2018)
  • Author(s): 川尻剛照
  • Organizer: 第50回日本動脈硬化学会総会・学術集会
  • Invited
• [Book] 虚血性心疾患 識る・診る・治す・防ぐ (2018)
  • Author(s): 川尻剛照、山岸正和
  • Total Pages: 400
  • Publisher: 中山書店
  • ISBN: 978-4-521-74584-8
• [Book] 循環器疾患最新の治療2018-2019 (2018)
  • Author(s): 川尻剛照、山岸正和
  • Total Pages: 540
  • Publisher: 南江堂
  • ISBN: 978-4-524-25218-3