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ANGPTL3的遗传学和药理学失活与心血管疾病
Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease


Frederick E. Dewey ... 心脑血管疾病 • 2017.07.20

ANGPTL3会是下一个PCSK9吗

 

王琰*,宋保亮*

武汉大学生命科学学院

* 通讯作者

 

ANGPTL基因家族编码一类分泌性蛋白,最近一系列研究发现它们在血脂代谢中发挥重要作用。2002年Koishi等首先发现小鼠中Angptl3基因缺失导致低脂血症1。2009年Helen Hobbs等发现ANGPTL3的突变与人的三酰甘油水平显著相关2。随后哈佛医学院等单位联合发现4例ANGPTL3纯合子功能缺失患者,他们均具有广谱的低脂血症(低LDL-C、HDL-C和三酰甘油)、健康状况良好且正常生育,提示ANGPTL3是一个安全的降血脂药物靶点3。今年4月JACC报道ANGPTL3功能失活突变体显著降低心血管疾病发病率4

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摘要


背景

目前已发现,血管生成素样蛋白3基因(ANGPTL3)的功能缺失变异型与三酰甘油、低密度脂蛋白(LDL)胆固醇以及高密度脂蛋白(HDL)胆固醇血浆水平降低相关。但尚不明确ANGPTL3的此类变异型或治疗性拮抗作用是否与动脉粥样硬化性心血管疾病风险降低相关。

 

方法

我们对DiscovEHR人类遗传学研究中的58,335例参与者进行了ANGPTL3外显子测序。我们对DiscovEHR研究中的13,102例患者和40,430例对照,检测了ANGPTL3功能缺失变异型和血脂水平以及冠心病的关系,并且还纳入了4项人群研究中的23,317例患者和107,166例对照,对其进行随访研究。我们还在血脂异常的小鼠中及三酰甘油和LDL胆固醇水平升高的健康人类志愿者中,检测了人单克隆抗体(evinacumab,在小鼠中拮抗Angptl3,在人类中拮抗ANGPTL3)的效果。

 

结果

在DiscovEHR研究中,杂合子型ANGPTL3功能缺失变异型参与者的血清三酰甘油、HDL胆固醇以及LDL胆固醇显著低于没有变异型的参与者。功能缺失变异型存在于0.33%的冠心病患者和0.45%的对照(校正比值比,0.59;95%置信区间[CI],0.41~0.85;P=0.004)。这些结果在随访研究中得到了证实。在血脂异常的小鼠中,和对照抗体相比,用evinacumab抑制Angptl3导致了动脉粥样硬化斑块面积的较大幅缩小、坏死物质含量的较大幅降低。在人类中,evinacumab的作用呈剂量依赖性,经安慰剂校正后,可使空腹三酰甘油水平降低达76%、LDL胆固醇水平降低达23%。

 

结论

人类ANGPTL3和小鼠Angptl3的遗传学或治疗性拮抗作用,与全部三种主要血脂成分水平降低及动脉粥样硬化性心脑血管疾病发生概率降低相关(由再生元制药公司[Regeneron Pharmaceuticals]等资助;在ClinicalTrials.gov注册号为NCT01749878)。





作者信息

Frederick E. Dewey, M.D., Viktoria Gusarova, Ph.D., Richard L. Dunbar, M.D., Colm O’Dushlaine, Ph.D., Claudia Schurmann, Ph.D., Omri Gottesman, M.D., Shane McCarthy, Ph.D., Cristopher V. Van Hout, Ph.D., Shannon Bruse, Ph.D., Hayes M. Dansky, M.D., Joseph B. Leader, B.A., Michael F. Murray, M.D., Marylyn D. Ritchie, Ph.D., H. Lester Kirchner, Ph.D., Lukas Habegger, Ph.D., Alex Lopez, M.S., John Penn, M.S., An Zhao, Ph.D., Weiping Shao, Ph.D., Neil Stahl, Ph.D., Andrew J. Murphy, Ph.D., Sara Hamon, Ph.D., Aurelie Bouzelmat, M.S., Rick Zhang, Ph.D., Brad Shumel, M.D., Robert Pordy, M.D., Daniel Gipe, M.D., Gary A. Herman, M.D., Wayne H.H. Sheu, M.D., Ph.D., I-Te Lee, M.D., Ph.D., Kae-Woei Liang, M.D., Xiuqing Guo, Ph.D., Jerome I. Rotter, M.D., Yii-Der I. Chen, Ph.D., William E. Kraus, M.D., Svati H. Shah, M.D., M.H.S., Scott Damrauer, M.D., Aeron Small, B.A., Daniel J. Rader, M.D., Anders Berg Wulff, M.D., Ph.D., Børge G. Nordestgaard, M.D., D.M.Sc., Anne Tybjærg-Hansen, M.D., D.M.Sc., Anita M. van den Hoek, Ph.D., Hans M.G. Princen, Ph.D., David H. Ledbetter, Ph.D., David J. Carey, Ph.D., John D. Overton, Ph.D., Jeffrey G. Reid, Ph.D., William J. Sasiela, Ph.D., Poulabi Banerjee, Ph.D., Alan R. Shuldiner, M.D., Ingrid B. Borecki, Ph.D., Tanya M. Teslovich, Ph.D., George D. Yancopoulos, M.D., Ph.D., Scott J. Mellis, M.D., Ph.D., Jesper Gromada, Ph.D., D.M.Sc., and Aris Baras, M.D.
From Regeneron Genetics Center (F.E.D., C.O., C.S., O.G., S.M., C.V.V.H., S.B., L.H., A.L., J.P., N.S., A.J.M., J.D.O., J.G.R., A.R.S., I.B.B., T.M.T., G.D.Y., S.J.M., A. Baras) and Regeneron Pharmaceuticals (V.G., H.M.D., A.Z., W.S., N.S., A.J.M., S.H., A. Bouzelmat, R.Z., B.S., R.P., D.G., G.A.H., W.J.S., P.B., G.D.Y., S.J.M., J.G.) Tarrytown, NY; the Department of Medicine, Division of Translational Medicine and Human Genetics (R.L.D.), and Departments of Surgery (S.D.) and Genetics and Medicine (A.S., D.J.R.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, and Geisinger Health System, Danville (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.) — both in Pennsylvania; the Division of Endocrinology and Metabolism, Department of Internal Medicine (W.H.H.S., I.-T.L.) and Cardiovascular Center (K.-W.L.), Taichung Veterans General Hospital, Institute of Medical Technology, National Chung-Hsing University (W.H.H.S.), School of Medicine, Chung Shan Medical University (I.-T.L.), and the Department of Medicine, China Medical University (K.-W.L.), Taichung, and School of Medicine, National Yang-Ming University (W.H.H.S., I.-T.L., K.-W.L.), and School of Medicine, National Defense Medical Center (W.H.H.S.), Taipei — all in Taiwan; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor–UCLA Medical Center, Torrance, CA (X.G., J.I.R., Y.-D.I.C.); the Division of Cardiology, Department of Medicine, Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC (W.E.K., S.H.S.); the Department of Clinical Biochemistry, Rigshospitalet (A.B.W., B.G.N., A.T.-H.), the Copenhagen General Population Study (B.G.N., A.T.-H.) and Department of Clinical Biochemistry (B.G.N.), Herlev and Gentofte Hospital, and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, and Faculty of Health and Medical Sciences, University of Copenhagen (B.G.N., A.T.-H.) — all in Copenhagen; and TNO Metabolic Health Research, Gaubius Laboratory, Leiden, the Netherlands (A.M.H., H.M.G.P.). Address reprint requests to Dr. Dewey at Regeneron Genetics Center, 777 Old Saw Mill River Rd., Tarrytown, NY 10591, or at frederick.dewey@regeneron.com.

 

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