血管生成素样蛋白3的基因和药物失活与心血管疾病
Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.
作者信息
Dewey Frederick E, Gusarova Viktoria, Dunbar Richard L, O'Dushlaine Colm, Schurmann Claudia, Gottesman Omri, McCarthy Shane, Van Hout Cristopher V, Bruse Shannon, Dansky Hayes M, Leader Joseph B, Murray Michael F, Ritchie Marylyn D, Kirchner H Lester, Habegger Lukas, Lopez Alex, Penn John, Zhao An, Shao Weiping, Stahl Neil, Murphy Andrew J, Hamon Sara, Bouzelmat Aurelie, Zhang Rick, Shumel Brad, Pordy Robert, Gipe Daniel, Herman Gary A, Sheu Wayne H H, Lee I-Te, Liang Kae-Woei, Guo Xiuqing, Rotter Jerome I, Chen Yii-Der I, Kraus William E, Shah Svati H, Damrauer Scott, Small Aeron, Rader Daniel J, Wulff Anders Berg, Nordestgaard Børge G, Tybjærg-Hansen Anne, van den Hoek Anita M, Princen Hans M G, Ledbetter David H, Carey David J, Overton John D, Reid Jeffrey G, Sasiela William J, Banerjee Poulabi, Shuldiner Alan R, Borecki Ingrid B, Teslovich Tanya M, Yancopoulos George D, Mellis Scott J, Gromada Jesper, Baras Aris
机构信息
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.).
出版信息
N Engl J Med. 2017 Jul 20;377(3):211-221. doi: 10.1056/NEJMoa1612790. Epub 2017 May 24.
BACKGROUND
Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.
METHODS
We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol.
RESULTS
In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%.
CONCLUSIONS
Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).
背景
血管生成素样3基因（ANGPTL3）的功能丧失变异与血浆甘油三酯、低密度脂蛋白（LDL）胆固醇和高密度脂蛋白（HDL）胆固醇水平降低有关。目前尚不清楚此类变异或ANGPTL3的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58335名参与者的ANGPTL3外显子进行了测序。我们在DiscovEHR研究的13102例病例患者和40430名对照中，对ANGPTL3功能丧失变异与血脂水平及冠状动脉疾病进行了关联测试，并在四项人群研究的23317例病例患者和107166名对照中进行了后续研究。我们还测试了人源单克隆抗体evinacumab对血脂异常小鼠体内的Angptl3以及对甘油三酯或LDL胆固醇水平升高的健康人类志愿者体内的ANGPTL3的作用。
结果
在DiscovEHR研究中，ANGPTL3存在杂合功能丧失变异的参与者，其血清甘油三酯、HDL胆固醇和LDL胆固醇水平显著低于没有这些变异的参与者。在0.33%的冠状动脉疾病病例患者和0.45%的对照中发现了功能丧失变异（校正比值比，0.59；95%置信区间，0.41至0.85；P=0.004）。这些结果在后续研究中得到了证实。在血脂异常小鼠中，用evinacumab抑制Angptl3导致动脉粥样硬化病变面积和坏死内容物的减少幅度大于对照抗体。在人类中，evinacumab导致空腹甘油三酯水平经安慰剂校正后呈剂量依赖性降低，降幅高达76%，LDL胆固醇水平降幅高达23%。
结论
人类中ANGPTL3的基因和治疗性拮抗作用以及小鼠中Angptl3的拮抗作用与所有三种主要脂质成分水平降低以及动脉粥样硬化性心血管疾病几率降低相关。（由再生元制药公司等资助；ClinicalTrials.gov编号，NCT01749878。）
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