Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
J Am Coll Cardiol. 2013 Jan 29;61(4):427-436. doi: 10.1016/j.jacc.2012.08.1026. Epub 2012 Dec 19.
The aim of this study was to test the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced high-density lipoprotein (HDL) cholesterol.
Elevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease.
A total of 73,513 subjects from Copenhagen were genotyped, of whom 11,984 had ischemic heart disease diagnosed between 1976 and 2010. Fifteen genetic variants were selected, affecting: 1) nonfasting remnant cholesterol alone; 2) nonfasting remnant cholesterol and HDL cholesterol combined; 3) HDL cholesterol alone; or 4) low-density lipoprotein (LDL) cholesterol alone as a positive control. The variants were used in a Mendelian randomization design.
The causal odds ratio for a 1 mmol/l (39 mg/dl) genetic increase of nonfasting remnant cholesterol was 2.8 (95% confidence interval [CI]: 1.9 to 4.2), with a corresponding observational hazard ratio of 1.4 (95% CI: 1.3 to 1.5). For the ratio of nonfasting remnant cholesterol to HDL cholesterol, corresponding values were 2.9 (95% CI: 1.9 to 4.6) causal and 1.2 (95% CI 1.2 to 1.3) observational for a 1-U increase. However, for HDL cholesterol, corresponding values were 0.7 (95% CI: 0.4 to 1.4) causal and 1.6 (95% CI: 1.4 to 1.7) observational for a 1 mmol/l (39 mg/dl) decrease. Finally, for LDL cholesterol, corresponding values were 1.5 (95% CI: 1.3 to 1.6) causal and 1.1 (95% CI: 1.1 to 1.2) observational for a 1 mmol/l (39 mg/dl) increase.
A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials.
本研究旨在验证以下假设，即非空腹残余胆固醇升高是缺血性心脏病的一个因果风险因素，独立于高密度脂蛋白（HDL）胆固醇降低。
升高的残余胆固醇与富含甘油三酯的脂蛋白水平升高以及 HDL 胆固醇降低有关，所有这些都与缺血性心脏病有关。
共对来自哥本哈根的 73513 名受试者进行了基因分型，其中 11984 名受试者在 1976 年至 2010 年间被诊断为缺血性心脏病。选择了 15 种遗传变异，影响：1）非空腹残余胆固醇单独；2）非空腹残余胆固醇和 HDL 胆固醇联合；3）HDL 胆固醇单独；或 4）低密度脂蛋白（LDL）胆固醇单独作为阳性对照。这些变体被用于孟德尔随机设计。
非空腹残余胆固醇每升高 1mmol/L（39mg/dl）的因果比值为 2.8（95%置信区间[CI]：1.9 至 4.2），相应的观察性危险比为 1.4（95%CI：1.3 至 1.5）。对于非空腹残余胆固醇与 HDL 胆固醇的比值，相应的数值分别为因果 2.9（95%CI：1.9 至 4.6）和观察 1.2（95%CI 1.2 至 1.3），对于每增加 1U。然而，对于 HDL 胆固醇，相应的值分别为因果 0.7（95%CI：0.4 至 1.4）和观察 1.6（95%CI：1.4 至 1.7），每降低 1mmol/L（39mg/dl）。最后，对于 LDL 胆固醇，相应的值分别为因果 1.5（95%CI：1.3 至 1.6）和观察 1.1（95%CI：1.1 至 1.2），每增加 1mmol/L（39mg/dl）。
非空腹残余胆固醇升高 1mmol/L（39mg/dl）与缺血性心脏病的因果风险增加 2.8 倍相关，独立于 HDL 胆固醇降低。这意味着富含甘油三酯的脂蛋白颗粒中胆固醇含量的升高会导致缺血性心脏病。然而，由于研究中遗传变异的多效性影响不能完全排除，因此需要使用其他遗传变异和/或随机干预试验来证实这些发现。
