Investigations of novel subtypes of high-density lipoprotein in relation to cardiometabolic traits, lifestyle factors, and cardiovascular disease in three US-based cohorts

心血管疾病(CVD)仍然是世界范围内的主要死亡原因。来自观察性研究的大量证据表明，以胆固醇浓度(HDL-C)或载脂蛋白AI浓度(ApoAI，高密度脂蛋白的主要蛋白质成分)衡量的高密度脂蛋白(HDL)与心血管疾病的风险呈负相关。然而，高密度脂蛋白是否与心血管疾病有因果关系仍是一个有争议的问题。高密度脂蛋白是一组在蛋白质组成、结构和功能特性上不同的异质颗粒。因此，新的高密度脂蛋白研究集中在高密度脂蛋白的功能上，以及开发新的测量方法来捕捉这些特性。与高密度脂蛋白相关的蛋白质(高密度脂蛋白蛋白质组)通过调节与酶和受体的相互作用，对高密度脂蛋白下游的功能特性和代谢产生强大的影响。为了更好地理解高密度脂蛋白相关蛋白的功能重要性，例如，可以基于定义的蛋白质的存在或不存在来定义高密度脂蛋白的亚型。例如，最近的一项研究报告称，只有不含任何载脂蛋白CIII(ApoCIII)的高密度脂蛋白与冠心病风险呈负相关，而含有载脂蛋白CIII的高密度脂蛋白与冠心病呈正相关。除了apoCIII，现代蛋白质组学方法已经鉴定出超过85种与高密度脂蛋白相关的蛋白质。关于特定蛋白质在脂类代谢、炎症和免疫中的作用，我们知道得很多。然而，关于含或不含这些蛋白质的高密度脂蛋白亚型与心脏代谢特征和心血管事件的关系却知之甚少。哈佛大学公共卫生学院营养系的Jensen教授的研究小组专注于评估和测量新的高密度脂蛋白亚型与心血管疾病的关系。本研究的目的有两个：1.在动脉粥样硬化的多种族研究中，探讨载脂蛋白CIII亚型与心脏代谢特征、可改变的生活方式因素和亚临床心血管疾病特征的关系。2.在《护士健康研究II》和《卫生专业人员随访研究》中，探讨20种新的高密度脂蛋白亚型与冠心病发病风险的关系。建议对几种新的、功能相关的高密度脂蛋白亚型与心脏代谢危险因素和心血管疾病的相关性进行研究，这将促进对高密度脂蛋白在心血管疾病病因中的作用的理解，并可能确定新的治疗靶点。

Cardiovascular diseases (CVD) continue to be the leading causes of death worldwide. Ample evidence from observational studies indicates that high-density lipoprotein (HDL), as measured by either the concentration of cholesterol (HDL-C) or the concentration of apolipoprotein AI (apoAI, the main protein component of HDL) is inversely associated with the risk for CVD. However, whether HDL is causally related to CVD remains a matter of debate. HDL is increasingly recognized as a heterogeneous group of particles varying in protein composition, structure, and functional properties. Accordingly, new HDL research is focused on HDL functions, and the development of novel measures that capture such properties. Proteins that associate with HDL (the HDL proteome) have powerful impact on the downstream functional properties and metabolism of HDL by mediating interactions with enzymes and receptors. To better understand the functional importance of HDL-associated proteins, it is for instance possible to define subtypes of HDL based on the presence or absence of defined proteins. As an example, a recent study reported that only HDL that did not contain any apolipoprotein CIII (apoCIII) was inversely associated with risk of coronary heart disease (CHD), whereas HDL containing apoCIII was positively associated with CHD. Besides apoCIII, modern proteomic approaches have identified more than 85 proteins that are associated with HDL. Much is known about the role of the specific proteins in lipid metabolism, inflammation, and immunity. However, little is known about the relation of HDL subtypes containing or lacking these proteins to cardiometabolic traits and cardiovascular events. The research group of Prof. Jensen at the Department of Nutrition at the Harvard T.H. Chan School of Public Health focuses on the evaluation and measurement of new HDL subtypes with respect to their association with CVD. The aims of the proposed research project are twofold: 1. To investigate associations of HDL subtypes containing vs. lacking apoCIII with cardiometabolic traits, modifiable lifestyle factors and subclinical CVD traits in the Multi-Ethnic Study of Atherosclerosis. 2. To investigate associations of 20 novel HDL subtypes with the risk for incident CHD in the Nurses Health Study II and Health Professionals Follow-up Study. The proposed investigation of several new, functionally relevant, HDL subtypes with respect to their association with cardiometabolic risk factors and CVD shall foster the understanding of the role of HDL in the etiology of CVD, and might potentially identify novel treatment targets.