15万人参与的研究揭示:单独提高“好胆固醇”,并不一定好
2017/11/21
人体胆固醇也有“好”、“坏”之分:“好胆固醇”能够保护心脏,“坏胆固醇”太多会增加心脏病危险。那么,提高“好胆固醇”是不是对心血管疾病有积极影响呢?11月15日,《JAMA Cardiology》杂志刊文揭示了一项以15万名中国成年人为样本的研究成果,给出了否定的答案。


这一研究由牛津大学、北京大学、中国医学科学院的科学家们联合完成,他们通过阻断一种与新陈代谢相关的重要蛋白质,以提高“好”胆固醇浓度,然而结果却表明,这并不能预防心脏病或者中风。

这一研究由来自于牛津大学、北京大学、中国医学科学院的科学家们联合完成,他们将关注点放在胆固醇酯转运蛋白(CETP)上,一种负责在不同脂蛋白之间转移胆固醇的蛋白质。

“好坏”胆固醇

科学家们将关注点放在胆固醇酯转运蛋白(CETP)上,这是一种负责在不同脂蛋白之间转移胆固醇的蛋白质。

理论上,抑制CETP能够提高高密度脂蛋白胆固醇(HDL-C,被认为是“好”胆固醇,负责输出胆固醇促进其代谢)的水平,并导致血脂发生其他系列变化。这是预防、治疗心血管疾病的一种潜在方法。然而,最新的研究却提醒我们:事实并非如此。

除了HDL-C,血液中还有另一种胆固醇:低密度脂蛋白胆固醇(LDL-C),被称为“坏”胆固醇(会携带胆固醇积存在动脉壁上,进而引发动脉硬化、血栓、中风等风险)。降低LDL-C(例如他汀类药物)已经被证实可以降低心脏病、中风的风险,但是提高HDL-C却成效有限,即便观察性研究已经显示HDL-C与心血管风险之间存在反向关系。

15万人的研究

那么,靶向CETP蛋白的药物是否能够改善心血管健康?研究团队希望通过改变CETP基因,模拟这一药物的治疗效果,从而评估“修改胆固醇”的治疗利弊。他们以15万中国人作为研究对象,历时10年随访。数据显示,超5000位参与者患有冠心病,19000个人出现中风。

结果发现,ETP基因突变会显著提高高密度脂蛋白胆固醇的浓度,但是并不会降低低密度脂蛋白胆固醇的水平。这意味着它并不会降低心血管疾病的风险,也不会对动脉粥样硬化斑块、动脉厚度以及糖尿病、肾脏等其他疾病产生影响。而且,抑制CETP蛋白,容易引发眼疾。

这项研究成果与最近公布的REVEAL临床试验(CETP抑制剂anacetrapib)一致。临床试验显示,CETP抑制剂对于心血管疾病的益处更多的关键点在于降低“坏胆固醇”上。

文章作者、牛津大学的Iona Millwood教授总结道:“我们的发现有助于阐明不同类型胆固醇的作用,并标明仅仅提高HDL-C(不降低LDL-C)的治疗策略并不能对心血管疾病产生积极的影响。

使用遗传数据预测新疗法

除了验证“提高好胆固醇”的疗效,该研究的另一大亮点在于利用遗传数据模拟药物临床试验,它可以预测新靶点的成效,从而减少药物开发的成本、合理优化项目的选择。

这种方法可能会广泛应用于大规模的临床试验之前,以此验证疾病致病机理。目前已知的数千种功能性基因变异可能代表了不同生物途径的潜在药物靶点。研究团队正在使用同样的方法来评估其他一些重要的治疗靶点。

牛津大学的Zhengming Chen教授认为,这项研究展示了大型前瞻性数据库(遗传信息、健康记录)研究的价值,可在全球不同的群体、地区进行,从而预测新药治疗的潜在益处或者危害。

参考资料:

Raising 'good' cholesterol fails to protect against heart disease

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

    Importance Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10−47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). Conclusions and Relevance CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test