Cholesterol Homeostasis in Framingham Offspring Study

描述（由申请人提供）：本申请的目的是研究使用胆固醇稳态测量的预测价值，以确定与既定危险因素相关的心血管疾病（CVD）高风险个体。具体目的是：1)量化血浆样本中胆固醇稳态循环指标[植物甾醇和胆固醇水平（胆固醇吸收的替代指标）和胆固醇前体（胆固醇合成率的替代指标）]，这些血浆样本来自Framingham后代研究参与者，他们被诊断为已建立的心血管疾病和/或50%颈动脉狭窄（N=165），未服用降脂药物，对照受试者的年龄、性别、体重指数、高血压和吸烟状况（n=330）；2)评估使用胆固醇稳态指标预测Framingham后代研究周期6参与者心血管疾病风险的有效性：a)建立植物甾醇、胆固醇和胆固醇前体循环水平的成人正常范围（N=3378）； b)确定植物甾醇、胆固醇和胆固醇前体水平与血浆脂质、脂蛋白和载脂蛋白水平之间的关系；胆固醇和胆固醇前体水平和选定的膳食摄入数据（能量、蛋白质、脂肪、饱和、单不饱和、多不饱和和反式脂肪酸、胆固醇、纤维和抗氧化剂补充剂），以及d)确定植物甾醇、胆固醇和胆固醇前体水平与CVD风险相关的选定基因型数据（载脂蛋白E、载脂蛋白A-IV、清除率受体B类1型[SRB1]和atp结合体[ABC] G5和ABCG8转运体的基因位点）之间的关系；3)监测Framingham后代研究队列在10年期间（1995-2005）的临床事件，并将这些数据与植物甾醇、胆固醇和胆固醇前体水平联系起来。胆固醇稳态测量将首先在特定目标#1中确定的受试者中进行量化，然后在特定目标#2中确定的受试者的平衡，由于使用单个血浆样品的气相色谱方法的发展，现在可以实现。这些数据将与该队列目前可获得的饮食、生化和基因型数据进行评估。拟议工作的结果将确定胆固醇吸收和合成标记物与心血管疾病结局之间的关系；建立胆固醇吸收和合成测量的参考值；并评估这些措施的预测价值，以确定相对于既定危险因素的高风险个体。

DESCRIPTION (provided by applicant): The objective of this application is to investigate the predictive value of using measures of cholesterol homeostasis to identify individuals at high risk of developing cardiovascular disease (CVD) relative to established risk factors. The specific aims are to 1) quantify circulating indicators of cholesterol homeostasis [levels of phytosterols and cholestanol (surrogate measures of cholesterol absorption) and cholesterol precursors (surrogate measures of cholesterol synthetic rates)] in plasma samples from Framingham Offspring Study participants diagnosed with established CVD and/or >50% carotid stenosis (N=165) not taking lipid-lowering medication and control subjects matched for age, sex, body mass index, hypertension and smoking status (n=330); 2) evaluate the validity of using indicators of cholesterol homeostasis to predict CVD risk in the Framingham Offspring Study-Cycle 6 participants by a) establishing adult normal ranges for circulating levels of phytosterol, cholestanol and cholesterol precursor (N=3378), b) defining the relationship between phytosterol, cholestanol and cholesterol precursor levels, and lipid, lipoprotein and apolipoprotein levels in plasma, c) defining the relationship between phytosterol, cholestanol and cholesterol precursor levels and selected dietary intake data (energy, protein, fat, saturated, monounsaturated, polyunsaturated and trans fatty acids, cholesterol, fiber and antioxidant supplements) and d) determining the relationship between phytosterol, cholestanol and cholesterol precursor levels and selected genotype data related to CVD risk (gene loci of apo E, apo A-IV, scavenger receptor class B type 1 [SRB1], and ATP-binding cassette [ABC] G5 and ABCG8 transporters); and 3) monitor clinical events in the Framingham Offspring Study cohort throughout a 10-year period (1995-2005) and relate these data to the phytosterol, cholestanol and cholesterol precursor levels. Measures of cholesterol homeostasis will be quantified first in subjects identified in specific aim #1 and then the balance of subjects identified in specific aim #2, achievable now due to the development of a gas chromatographic method using a single plasma sample. These data will be assessed relative to dietary, biochemical and genotype data currently available for the cohort. The results of the proposed work will define the relationship between markers of cholesterol absorption and synthesis, and CVD outcomes; establish reference values for measures of cholesterol absorption and synthesis; and assess the predictive value of these measures to identify high risk individuals relative to established risk factors.