Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes
Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes
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DOI：
10.1056/nejmoa1604304
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发表时间：
2016-12-01
影响因子：
158.5
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
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作者：
Ference, Brian A.;Robinson, Jennifer G.;Sabatine, Marc S.
背景：原蛋白转换酶枯草杆菌-可可心9型(PCSK9)的药理抑制剂正在进行心血管疾病的临床试验。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的影响尚不清楚。方法我们使用PCSK9和3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR；他汀类药物的靶标)编码基因的独立遗传变异组成的遗传评分作为工具，根据他们遗传的降低低密度脂蛋白胆固醇的等位基因数量，随机将来自14项研究的112,772名参与者分配到14,120例心血管疾病和10,635例糖尿病患者。我们比较了PCSK9和/或HMGCR变异所介导的低密度脂蛋白水平降低对心血管事件风险和糖尿病风险的影响。结果PCSK9和HMGCR变异对心血管事件风险的保护作用几乎相同，每分升低密度脂蛋白水平降低10毫克(0.26 mmol/升)：心血管事件的优势比，PCSK9的0.81(95%可信区间[CI]，0.74至0.89)，HMGCR的0.81(95%可信区间，0.72至0.90)。这两个基因的变异对糖尿病风险的影响也非常相似：低密度脂蛋白胆固醇每降低10毫克，PCSK9的优势比为1.11(95%CI，1.04~1.19)，HMGCR的优势比为1.13(95%CI，1.06~1.20)。糖尿病风险的增加仅限于两种评分的空腹血糖水平受损的人，而且其幅度低于对心血管事件的保护作用。当PCSK9和HMGCR变异体同时存在时，PCSK9变异体和HMGCR变异体对心血管事件和糖尿病的风险具有相加作用。结论在本研究中，PCSK9变异体与HMGCR变异体在降低单位低密度脂蛋白水平的心血管事件和糖尿病风险方面具有大致相同的效果。这些变异的影响是独立的和相加的。(由医学研究委员会和国家心肺血液研究所资助。)
BACKGROUNDPharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown.METHODSWe used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes.RESULTSVariants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes.CONCLUSIONSIn this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.)