Sequence variations in PCSK9, low LDL, and protection against coronary heart disease
Sequence variations in PCSK9, low LDL, and protection against coronary heart disease
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DOI：
10.1056/nejmoa054013
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发表时间：
2006-03-23
影响因子：
158.5
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
--
作者：
Cohen, JC;Boerwinkle, E;Hobbs, HH
背景
低密度脂蛋白（LDL）胆固醇的血浆水平较低与冠心病（CHD）风险降低相关，但终生降低血浆LDL胆固醇的影响尚不明确。我们在一大群人中研究了降低血浆LDL胆固醇水平的DNA序列变异对冠心病事件发生率的影响。
方法
我们根据前蛋白转化酶枯草杆菌蛋白酶/可馨型9丝氨酸蛋白酶基因（PCSK9）中是否存在与血浆LDL胆固醇水平降低相关的序列变异，在社区动脉粥样硬化风险研究中比较了15年间冠心病（心肌梗死、致命性冠心病或冠状动脉血运重建）的发生率。
结果
在接受检查的3363名黑人受试者中，2.6%在PCSK9基因中有无义突变；这些突变与平均LDL胆固醇降低28%以及冠心病风险降低88%相关（降低的P值为0.008；风险比为0.11；95%置信区间为0.02 - 0.81；P = 0.03）。在接受检查的9524名白人受试者中，3.2%在PCSK9基因中有序列变异，该变异与LDL胆固醇降低15%以及冠心病风险降低47%相关（风险比为0.50；95%置信区间为0.32 - 0.79；P = 0.003）。
结论
这些数据表明，即使在非脂质相关心血管危险因素患病率较高的人群中，终生适度降低血浆LDL胆固醇水平也与冠心病事件发生率的大幅降低相关。
BACKGROUNDA low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.METHODSWe compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.RESULTSOf the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).CONCLUSIONSThese data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.