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PCSK9和HMGCR的基因变异与心血管疾病和糖尿病的患病风险
Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes


Brian A. Ference ... 心脑血管疾病 糖尿病 • 2016.12.01

PCSK9:降低低密度脂蛋白胆固醇药物研发的新靶点

 

贾伟平

上海交通大学附属第六人民医院

 

低密度脂蛋白胆固醇(LDL-C)增高是动脉粥样硬化性心血管疾病(ASCVD,包括冠心病、缺血性卒中以及外周动脉疾病)的危险因素。2015年的一项荟萃分析显示,LDL-C每降低1 mmol/L,可分别降低女性及男性发生主要心血管事件风险16%和22%(RR值分别为0.84和0.78,99% CI分别为0.78~0.91和0.75~0.81)1。大量的观察性研究和临床试验也显示,降低LDL-C,可以显著减低心血管疾病(CVD)事件的发生2-5。他汀类药物是目前降低LDL-C治疗领域最成功的药物之一,其作用靶点是胆固醇合成过程途径的3-羟-3-甲基戊二酰辅酶A还原酶(HMGCR)。

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摘要


背景

前蛋白转化酶枯草溶菌素9(PCSK9)的药理学抑制剂治疗心血管疾病正在被临床试验评估。通过抑制PCSK9降低低密度脂蛋白(LDL)胆固醇水平对心血管事件或糖尿病风险产生的影响不明。

 

方法

我们使用由编码PCSK9和3-羟-3-甲基戊二酰辅酶A还原酶(HMGCR;他汀类的靶点)的基因中独立的遗传变异体组成的基因评分作为工具,根据其已遗传的降低LDL胆固醇的等位基因数目,对来自14项研究的112,772名参与者进行随机分组,这些参与者中有14,120例心血管事件和10,635例糖尿病。我们比较了由PCSK9HMGCR中变异体或两者合用介导的较低LDL胆固醇水平对心血管事件风险和糖尿病风险产生的效应。

 

结果

每降低10 mg/dL(0.26 mmol/L)LDL胆固醇水平,PCSK9HMGCR变异体都和几乎相同的心血管事件风险保护作用相关:对于PCSK9,心血管事件比值比为0.81(95%可信区间[CI],0.74~0.89),对于HMGCR,该值为0.81(95% CI为0.72~0.90)。这两个基因中变异体也和非常相似的糖尿病风险作用有关:每降低10 mg/dL LDL胆固醇,比值比对于PCSK9是1.11(95% CI为1.04~1.19),对于HMGCR是1.13(95% CI为1.06~1.20)。对于两个评分,增加的糖尿病风险限于空腹血糖水平受损人群,且在幅度上比心血管事件所受到的保护作用低。PCSK9HMGCR变异体两者一起存在时对心血管事件和糖尿病风险有叠加作用。

 

结论

在本研究中,每降低1个单位LDL胆固醇水平,PCSK9变异体对心血管事件和糖尿病风险的影响几乎与HMGCR变异体相同。这些变异体的作用是独立且叠加的(英国医学研究委员会[Medical Research Council]和美国国立心肺血液研究所[National Heart, Lung, and Blood Institute]资助)。





作者信息

Brian A. Ference, M.D., Jennifer G. Robinson, M.D., M.P.H., Robert D. Brook, M.D., Alberico L. Catapano, Ph.D., M. John Chapman, Ph.D., David R. Neff, D.O., Szilard Voros, M.D., Robert P. Giugliano, M.D., George Davey Smith, M.D., D.Sc., Sergio Fazio, M.D., Ph.D., and Marc S. Sabatine, M.D., M.P.H.
From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) — all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié–Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.). Address reprint requests to Dr. Ference at the Division of Cardiovascular Medicine, Wayne State University School of Medicine, UHC, 4H-34, Detroit, MI 48202, or at bference@med.wayne.edu.

 

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