动脉粥样硬化疾病分子遗传学研究
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摘要
依折麦布是一种选择性胆固醇吸收抑制剂,其作用机制主要是阻断胆固醇的外源性吸收途径。依折麦布与辛伐他汀联合应用则可分别从胆固醇的内、外源性途径对血脂水平进行调节以达到最佳调脂效果,大量的基础和临床试验研究的发表证明了医学界对依折麦布药物降脂疗效的关注,本文即对目前已发表的,研究依折麦布联合辛伐他汀降脂疗效和安全性的随机对照试验进行荟萃分析。
系统检索PubMed.Cochrane Libraty、Embase三个电子数据库,并通过阅读相关综述及文章的参考文献进一步获取信息,两个作者独立阅读所有文献,按入选标准纳入试验,对目前已发表的,研究依折麦布联合辛伐他汀与辛伐他汀单独使用的疗效比较的随机对照试验进行荟萃分析。用随机效应模型计算标准化平均差(standardized mean differences,SMD)及其95%可信区间(CI),用以描述血脂(LDL-C、HDL-C、TC、TG)的净差值。
最终7个干预试验被纳入荟萃分析,研究对象共计4563人。荟萃分析显示,依折麦布联合辛伐他汀与单独口服辛伐他汀相比,血浆LDL-C水平下降SMD-15.12%,(95%CI：-19.50,-10.73,P<0.0001)具有显著性统计学差异,相似的统计学差异也见于血浆HDL-C(1.89％,95％CI:1.21,2.57,P<0.0001).TC(-13.5％, 95％CI:-17.32,-9.68,P<0.0001)、TG(-3.09％,95％CI:-4.40,.1.78,P<0.0001)。
经短期随即对照试验荟萃分析,依折麦布联合辛伐他汀相较于辛伐他汀单独应用能更有效的降低血脂水平,但是否能够降低临床终点事件发生率,尚需要更多的长期干预试验提供证据。
研究背景
在动脉粥样硬化发病机制中,单核细胞中的胆固醇和脂蛋白的水平要比血浆中的脂蛋白和胆固醇的水平重要,单核细胞中的胆固醇的水平直接影响泡沫细胞的形成,粥样斑块的发生发展。C型1类尼曼-匹克(Niemann-pick type C1, NPC1)是细胞晚期内体(late endosome, LE)中含有一个固醇感受域的跨膜糖蛋白,参与内源性胆固醇转运,主要存在于中枢神经系统、肝脏和单核细胞中,它能监测细胞胆固醇水平的变化,可能通过改变小泡转运方式或直接参与脂质跨膜转运来调节细胞脂质平衡。
研究目的
NPC1等位基因与冠心病发生是否有关联,并分析此基因因素在冠心病发生中的作用强度,以及与吸烟相互作用在冠心病发生中的作用。
对象和方法
本研究选择冠心病病例和社区对照人群分别873和864人,采用聚合酶链反应—限制性片段长度多态性(PCR-RFLP)法研究NPC1基因的多态性位点与冠心病遗传易感因素的关系。
研究结果
结果显示His215Arg位点与冠心病存在易感相关(OR 0.647,95% C10.428 to 0.980,P=0.039),并呈隐性遗传模式,与携带GT+TT基因型相比,GG的患者发生冠心病的危险性明显降低且具有统计学意义。而且在吸烟人群中,携带GG基因型与携带GT+TT基因型相比患冠心病的危险性低(P=0.0001)。
结论
以上的研究结果显示,在基因水平上,NPC1基因多态性与单核细胞脂质蓄积有关,且与吸烟相互作用在冠心病发生发展过程中起到一定的作用。
Objectives To study the evidence on the efficacy and safety of ezetimibe co-administrated with simvatatin compared to simvatatin monotherapy.
Design Meta-analysis of randomized controlled trials (RCTs).
Methods Three electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs.
Results A meta-analysis of seven randomized, double-blind, controlled trials (4563 people) showed that ezetimibe co-administrated with simvatatin was associated with a statistically significant mean reduction in LDL cholesterol (from baseline endpoint) of-15.12%, (95% CI:-19.50 to-10.73, P<0.0001) compared with simvatatin monotherapy. Significant changes were also found in HDL cholesterol (1.89%,95%CI:1.21 to 2.57, P<0.0001), total cholesterol (-13.5%,95%CI:-17.32 to-9.68, P<0.0001) and triglyceride levels (-3.09%,95%CI:-4.40 to-1.78, P<0.0001).
Conclusions Ezetimibe co-administrated with simvatatin is effective in reducing the lipid and lipoprotein levels relative to simvatatin monotherapy.
BACKGROUND:The protein of Niemann-pick type C1 gene (NPCl) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments and plays critical roles in vascular injure, which is involved in the progression of coronary heart disease. This study aims to investigate whether the single-nucleotide polymorphisms (SNPs) of NPC1 are associated with risk of coronary heart disease (CHD) and to investigate the interaction between NPCl with smoking on CHD.
METHODS:We performed a case-control study, including 873 patients with coronary heart disease (CHD) and 864 subjects without CHD as control. Polymorphisms of NPC1 gene were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).
RESULTS:Patients carrying the Arg215Arg had a decrease risk of CHD as compared with those carrying genotypes His215His and His215Arg in Chinese population (odds ratios 0.647,95%CI 0.428 to 0.980, P=0.039). Moreover in smokers, carriers of NPC1 His215His and His215Arg had significantly increased age-and sex-adjusted CHD.
CONCLUSIONS:These findings may provide evidence that in gene status NPC1 contributes to lipid accumulation in human macrophages and interacts with smoking environment factor in the pathogenesis of CHD.
系统检索PubMed.Cochrane Libraty、Embase三个电子数据库,并通过阅读相关综述及文章的参考文献进一步获取信息,两个作者独立阅读所有文献,按入选标准纳入试验,对目前已发表的,研究依折麦布联合辛伐他汀与辛伐他汀单独使用的疗效比较的随机对照试验进行荟萃分析。用随机效应模型计算标准化平均差(standardized mean differences,SMD)及其95%可信区间(CI),用以描述血脂(LDL-C、HDL-C、TC、TG)的净差值。
最终7个干预试验被纳入荟萃分析,研究对象共计4563人。荟萃分析显示,依折麦布联合辛伐他汀与单独口服辛伐他汀相比,血浆LDL-C水平下降SMD-15.12%,(95%CI：-19.50,-10.73,P<0.0001)具有显著性统计学差异,相似的统计学差异也见于血浆HDL-C(1.89％,95％CI:1.21,2.57,P<0.0001).TC(-13.5％, 95％CI:-17.32,-9.68,P<0.0001)、TG(-3.09％,95％CI:-4.40,.1.78,P<0.0001)。
经短期随即对照试验荟萃分析,依折麦布联合辛伐他汀相较于辛伐他汀单独应用能更有效的降低血脂水平,但是否能够降低临床终点事件发生率,尚需要更多的长期干预试验提供证据。
研究背景
在动脉粥样硬化发病机制中,单核细胞中的胆固醇和脂蛋白的水平要比血浆中的脂蛋白和胆固醇的水平重要,单核细胞中的胆固醇的水平直接影响泡沫细胞的形成,粥样斑块的发生发展。C型1类尼曼-匹克(Niemann-pick type C1, NPC1)是细胞晚期内体(late endosome, LE)中含有一个固醇感受域的跨膜糖蛋白,参与内源性胆固醇转运,主要存在于中枢神经系统、肝脏和单核细胞中,它能监测细胞胆固醇水平的变化,可能通过改变小泡转运方式或直接参与脂质跨膜转运来调节细胞脂质平衡。
研究目的
NPC1等位基因与冠心病发生是否有关联,并分析此基因因素在冠心病发生中的作用强度,以及与吸烟相互作用在冠心病发生中的作用。
对象和方法
本研究选择冠心病病例和社区对照人群分别873和864人,采用聚合酶链反应—限制性片段长度多态性(PCR-RFLP)法研究NPC1基因的多态性位点与冠心病遗传易感因素的关系。
研究结果
结果显示His215Arg位点与冠心病存在易感相关(OR 0.647,95% C10.428 to 0.980,P=0.039),并呈隐性遗传模式,与携带GT+TT基因型相比,GG的患者发生冠心病的危险性明显降低且具有统计学意义。而且在吸烟人群中,携带GG基因型与携带GT+TT基因型相比患冠心病的危险性低(P=0.0001)。
结论
以上的研究结果显示,在基因水平上,NPC1基因多态性与单核细胞脂质蓄积有关,且与吸烟相互作用在冠心病发生发展过程中起到一定的作用。
Objectives To study the evidence on the efficacy and safety of ezetimibe co-administrated with simvatatin compared to simvatatin monotherapy.
Design Meta-analysis of randomized controlled trials (RCTs).
Methods Three electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs.
Results A meta-analysis of seven randomized, double-blind, controlled trials (4563 people) showed that ezetimibe co-administrated with simvatatin was associated with a statistically significant mean reduction in LDL cholesterol (from baseline endpoint) of-15.12%, (95% CI:-19.50 to-10.73, P<0.0001) compared with simvatatin monotherapy. Significant changes were also found in HDL cholesterol (1.89%,95%CI:1.21 to 2.57, P<0.0001), total cholesterol (-13.5%,95%CI:-17.32 to-9.68, P<0.0001) and triglyceride levels (-3.09%,95%CI:-4.40 to-1.78, P<0.0001).
Conclusions Ezetimibe co-administrated with simvatatin is effective in reducing the lipid and lipoprotein levels relative to simvatatin monotherapy.
BACKGROUND:The protein of Niemann-pick type C1 gene (NPCl) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments and plays critical roles in vascular injure, which is involved in the progression of coronary heart disease. This study aims to investigate whether the single-nucleotide polymorphisms (SNPs) of NPC1 are associated with risk of coronary heart disease (CHD) and to investigate the interaction between NPCl with smoking on CHD.
METHODS:We performed a case-control study, including 873 patients with coronary heart disease (CHD) and 864 subjects without CHD as control. Polymorphisms of NPC1 gene were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).
RESULTS:Patients carrying the Arg215Arg had a decrease risk of CHD as compared with those carrying genotypes His215His and His215Arg in Chinese population (odds ratios 0.647,95%CI 0.428 to 0.980, P=0.039). Moreover in smokers, carriers of NPC1 His215His and His215Arg had significantly increased age-and sex-adjusted CHD.
CONCLUSIONS:These findings may provide evidence that in gene status NPC1 contributes to lipid accumulation in human macrophages and interacts with smoking environment factor in the pathogenesis of CHD.
引文
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[1]Sudhop, T., Lutjohann, D., Kodal, A., et al., Inhibition of intestinal cholesterol absorption by ezetimibe in humans, Circulation 2002,106:1943-1948.
[2]Patrick, J. E., Kosoglou, T., Stauber, K. L., et al., Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects, Drug Metab Dispos 2002,30:430-437.
[3]Garcia-Calvo, M., Lisnock, J., Bull, H. G., et al., The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1), Proc Natl Acad Sci U S A 2005,102:8132-8137.
[4]Wang, J., Chu, B. B., Ge, L., et al., Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption, J Lipid Res 2009,50:1653-1662.
[5]Tang, W., Ma, Y., Jia, L., et al., Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8, J Lipid Res 2009,50:293-300.
[6]Davis, H. R., Jr.,Altmann, S. W., Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter, Biochim Biophys Acta 2009,1791:679-683.
[7]Sane, A. T., Sinnett, D., Delvin, E., et al., Localization and role of NPC1L1 in cholesterol absorption in human intestine, J Lipid Res 2006,47:2112-2120.
[8]Weinglass, A. B., Kohler, M., Schulte, U., et al., Extracellular loop C of NPC1L1 is important for binding to ezetimibe, Proc Natl Acad Sci U S A 2008,105:11140-11145.
[9]Valasek, M. A., Repa, J. J., Quan, G., et al., Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters, Am J Physiol Gastrointest Liver Physiol 2008,295:G813-822.
[10]Turley, S. D., The role of Niemann-Pick C1-Like 1 (NPC1L1) in intestinal sterol absorption, J Clin Lipidol 2008,2:S20-S28.
[11]Petersen, N. H., Faergeman, N. J., Yu, L., et al., Kinetic imaging of NPC1L1 and sterol trafficking between plasma membrane and recycling endosomes in hepatoma cells, J Lipid Res 2008,49: 2023-2037.
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