HDL Proteins and Coronary Heart Disease

描述（由申请人提供）：高密度脂蛋白（HDL）被认为是血浆中一组结构和功能显著异质的颗粒。然而，HDL在流行病学研究以及开发和测试治疗以减少冠心病（CHD）中被视为同质脂蛋白类型。HDL-胆固醇或其主要蛋白apoA-I浓度是CHD的强逆危险因素。然而，一个共识正在形成，即需要了解人类HDL的多样性，以在低或高HDL水平的意义以及如何使用HDL信息来开发可以降低CVD的治疗方法方面取得进展。HDL存在于过多的亚群中，这些亚群由与CHD风险具有不同关系的蛋白质含量定义。例如，具有apoC-III的HDL的浓度预测CVD的风险增加而不是降低，并且具有apoC-III的HDL缺乏总HDL和不具有apoC-III的HDL所具有的保护功能。某些HDL亚型的异常功能和CHD风险增加的一致性支持载脂蛋白改变HDL功能的关键概念，并且这种改变的功能涉及HDL类型对动脉粥样硬化和CVD发病率的影响。 第一个具体目的是测量HDL亚型的血浆浓度，所述HDL亚型由其含有或不含有通过蛋白质组学在HDL中发现的至少60种蛋白质中的一种或多种来定义。每种蛋白质都具有与HDL或CHD相关的已知功能，例如对参与动脉粥样硬化的细胞的作用;胆固醇转移到细胞和HDL以及从细胞和HDL转移胆固醇;抑制氧化或炎症;止血;和先天免疫。每种蛋白质将定义一对HDL亚型，其具有或不具有特定蛋白质，例如具有apoC-III的HDL，不具有apoC-III的HDL。我们将确定每种新型HDL的浓度范围及其在代表性人群样本中随时间的稳定性。我们将通过脂质和蛋白质含量以及大小来表征HDL类型。我们预计，数据简化将产生一组20对或更少的HDL类型，用于第二个特定目标，以评估两个前瞻性美国女性队列（护士健康研究II）和男性队列（健康专业人员随访研究）中CHD的风险。在第三个具体目标中，我们将单独选择与风险有独立和强关系的HDL类型，并增加相对风险的大小，不利或保护。我们将设计一个个性化的HDL风险指数，结合保护性，非保护性和不良类型的信息。我们还将研究根据蛋白质的已知主要功能分组的HDL亚型的指数，例如胆固醇转移，止血，氧化等，这可能与一个人的CHD的特定病因有关。我们将测试与新的HDL类型一起构建的指数在标准CHD风险预测模型中的作用。我们的最终目标是发现可用于预测CHD风险的指标;评估对饮食和药物治疗的反应;并发现新的特异性HDL靶点用于开发预防CHD的药物。

DESCRIPTION (provided by applicant): High density lipoproteins (HDL) are being recognized as a remarkably structurally and functionally heterogeneous group of particles in blood plasma. However, HDL is treated as a homogeneous lipoprotein type in epidemiological studies and in development and testing of treatments to reduce coronary heart disease (CHD). The concentration of HDL-cholesterol or its major protein apoA-I is a strong inverse risk factor for CHD. However, a consensus is developing that knowledge of the diversity of HDL in humans is needed to make progress on the meaning of a low or a high HDL level and how to use information on HDL to develop treatments that can lower CVD. HDL exists in a plethora of subpopulations defined by content of proteins that have diverse relations to risk of CHD. For example, the concentration of HDL that has apoC-III predicts increased rather than decreased risk of CVD, and HDL with apoC-III lacks protective functions possessed by the total HDL and HDL that does not have apoC-III. Concordance of abnormal function and increased CHD risk of certain HDL subtypes supports the key concept that apolipoproteins alter the function of HDL, and that this altered function is involved in effects of the HDL types on atherosclerosis and incidence of CVD. The first specific aim is to measure the plasma concentrations of HDL subtypes defined by their containing or not containing one or more of at least 60 proteins that have been found in HDL by proteomics. Each protein has a known function related to HDL or CHD such as effects on cells that participate in atherosclerosis; cholesterol transfer to and from cells and HDL; inhibiting oxidation or inflammation; hemostasis; and innate immunity. Each protein will define a pair of HDL subtypes, that either have or do not have a specific protein, e.g HDL with apoC-III, HDL without apoC-III. We will determine for each new type of HDL the range of its concentration and its stability over time in samples from representative populations. We will characterize the HDL types by lipid and protein contents and by size. We anticipate that data reduction will produce a panel of 20 or fewer pairs of HDL types for the second specific aim to evaluate for risk of CHD in two prospective US cohorts of women (Nurses' Health Study II) and men (Health Professionals Follow-up Study). In the third specific aim, we will select HDL types individually that have independent and strong relations to risk, and that add to the magnitude of relative risk, adverse or protective. We will devise a personalized risk index of HDL that combines the information on protective, nonprotective, and adverse types. We will also study indexes of HDL subtypes grouped according to the known major function of the protein, e.g. cholesterol transfer, hemostasis, oxidation, etc. This could be relevant to the particular etiology of a person's CHD. We will test how much the indexes built with novel HDL types together add to standard CHD risk prediction models. Our ultimate aim is to discover indexes that are useful in predicting CHD risk; evaluating response to diet and drug treatments; and discovering new specific HDL targets for development of drugs to prevent CHD.