前蛋白转化酶枯草溶菌素9与颈动脉粥样硬化进展关系的研究

Cardiovascular disease (CVD) events, including coronary heart disease and stroke, often occur in individuals without prior symptoms. Identifying more individuals who are asymptomatic and clinically free of CVD but at sufficiently high risk for a future CVD event has been recognized as the key element for primary prevention. Atherosclerosis which is fundamental to the occurrence of CVD could be reflected by non-invasively evaluating carotid atherosclerosis. Although we possess potent and effective new medications, a considerable residual burden of cardiovascular risk remains. Even giving intensive statin therapy to patients with high cardiovascular risk, the residual risk remains at 20%. The most important reason for this is that the progression of atherosclerosis in human arteries is still not entirely clear. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the ninth member of the proprotein convertase family and is related to proteinase K. PCSK9 is a circulating protein that impairs LDL clearance by promoting the LDL receptor degradation. Previous studies have demonstrated that PCSK9 is associated with LDL-C level and future cardiovascular risk. In addition, PCSK9 has emerged as a new pharmacological target for hypercholesterolemia, and different PCSK9 inhibitors are now evaluated in clinical trials. However, whether PCSK9 affects the progression of subclinical atherosclerosis is still unknown. This study is a 5-year population-based cohort study, which includes 1011 individuals, 440 men and 571 women free of CVD, aged from 50 to 79 years at baseline. All the 1011 individuals underwent twice B-mode ultrasound examinations of carotid arteries in 2007 and 2012, and have complete data on traditional cardiovascular risk factors from the two surveys conducted in 2007 and 2012. In this study, we will measure plasma PCSK9 concentration and genotype. The aims of this study focus on two aspects: 1) to investigate the association between baseline PCSK9 concentration and 5-year progression of carotid atherosclerosis, and further evaluate the additional predictive ability of baseline PCSK9 concentration beyond traditional risk factors for the progression of carotid atherosclerosis, 2) to evaluate the effects of PCSK9 gene mutation on PCSK9 concentration, on the progression of carotid atherosclerosis, and on the association between PCSK9 concentration and the progression of carotid atherosclerosis. We consider that clarifying these questions will provide evidence for the etiology of atherosclerosis and early prevention and treatment of CVD.

既往研究和我们的前期研究结果均表明目前已知的危险因素对动脉粥样硬化（AS）进展的解释有限。前蛋白转化酶枯草溶菌素9（PCSK9）通过阻止LDL受体再循环至肝细胞膜表面，减少可用的LDL受体数量，从而升高LDL-C。PCSK9已成为潜在的致AS的危险因素，同时也是新的降LDL-C药物靶点。然而，研究表明PCSK9还与其它危险因素相关，其是否具有独立于LDL-C之外的致AS进展的作用目前还尚不明确。本研究拟采用队列研究和巢式病例对照研究设计，前瞻性随访5年（2007-2012），研究人群为1011名基线无心血管病史的社区人群，且均已完成2次间隔5年的颈动脉超声检查、传统危险因素调查和血样收集。本研究将测量基线血样的PCSK9浓度和基因分型。研究目标：①探索基线PCSK9浓度与颈动脉粥样硬化进展的关系，并基于模型评价浓度对进展的预测能力；②探索PCSK9基因多态性与浓度的关系、与AS进展的关系。

既往研究表明目前已知的危险因素对动脉粥样硬化（AS）进展的解释有限，前蛋白转化酶枯草溶菌素9（PCSK9）已成为潜在的致AS的危险因素。虽然既往研究发现PCSK9与其它传统的致动脉粥样硬化危险因素相关，但其是否具有独立于LDL-C之外的致AS进展的作用在本研究开展之前还尚不明确。本研究是国际上首次利用前瞻性队列研究的方法，在1363人的队列人群中证实了基线血浆PCSK9浓度与10年新发颈动脉斑块及其总面积之间的关联性，且发现这个关联性是独立于LDL-C的，我们的研究发现说明PCSK9除了通过影响LDL-C的代谢这一条途径之外，还可能存在其它致动脉粥硬化的途径。这也从一定程度上解释了为何PCSK9抑制剂能够在他汀药物的基础之上能够进一步大幅度地降低心血管事件的发生率。本研究结果在发表之后，得到瑞典研究者的验证，他们在更大的队列人群中（4232人）发现基线PCSK9浓度能够预测未来15年心血管事件的发生，这一关联也是独立于LDL-C的。本研究的关键数据为1363例队列人群2002年心血管疾病传统危险因素、PCSK9浓度和ApoCIII浓度数据以及2002年和2012年两次颈动脉超声检查数据。本研究为理解人类动脉粥样硬化发生发展提供了新的线索；为进一步探索PCSK9致动脉粥样硬化的途径提供了新的依据，未来研究应该关注PCSK9独立于LDL-C和其它传统血脂指标之外的致动脉粥样硬化作用；本研究结果也在一定程度上为PCSK9抑制剂在我国人群的应用提供了线索和基础数据。在本项目资助下，本人以第一作者或责任作者身份发表英文论著文章8篇，所有文章均标注本项目资助，另外尚有两篇英文文章在投稿过程中。已发表的文章中，SCI文章有7篇，累积影响因子30.6分，Google Scholar累积他引77次。4分以上SCI文章5篇，5分以上SCI文章3篇。共4篇文章获得国际专家专题评述或国际学术媒体转载评述。在本项目资助期间，本人获得英国牛顿国际学者基金（10万英镑）并入选首批北京市医管局“青苗计划”；成为SCI杂志Medicine的编委会成员和多家SCI杂志的审稿人。培养博士研究生1名，硕士研究生2名，均已顺利毕业。项目投入经费23万元，支出22.97万元，剩余322元。本项目执行期间，申请经费变更一次，各项支出符合变更后的经费预算。

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