Cholesterol Homeostasis in Framingham Offspring Study

描述(由申请人提供)：本申请的目的是调查使用胆固醇稳态测量来识别与既定风险因素相关的心血管疾病(CVD)高危人群的预测价值。具体目标是：1)量化血浆样本中胆固醇稳态的循环指标[植物类固醇和胆固醇水平(替代胆固醇吸收的指标)和胆固醇前体(替代胆固醇合成率的指标)]，这些样本来自弗雷明翰后代研究参与者，被诊断为确诊为心血管疾病和/或颈动脉狭窄的50%(N=165)，以及年龄、性别、体重指数、高血压和吸烟状况匹配的对照组(n=330)；2)通过a)建立成人循环中植物甾醇、胆甾醇和胆固醇前体水平的正常范围(N=3378)，b)确定植物甾醇、胆固醇和胆固醇前体水平与血浆中脂质、脂蛋白和载脂蛋白水平之间的关系，c)定义植物甾醇、胆固醇和胆固醇前体水平与选定的饮食摄入数据(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)之间的关系，评估使用胆固醇稳态指标来预测第六个弗雷明翰子代研究周期参与者心血管疾病风险的有效性。与心血管疾病风险相关的胆固醇和胆固醇前体水平和选定的基因型数据(载脂蛋白E、载脂蛋白A-IV、清道夫受体B型1[SRB1]和三磷酸腺苷结合盒[ABC]G5和ABCG8转运体的基因座)；以及3)在10年内(1995-2005年)监测弗雷明翰后代研究队列中的临床事件，并将这些数据与植物类固醇、胆固醇和胆固醇前体水平联系起来。胆固醇稳态的测量将首先在特定目标#1中确定的受试者中量化，然后在特定目标#2中确定的受试者的平衡中进行量化，这一点现在可以实现，因为开发了一种使用单一血浆样本的气相色谱方法。这些数据将根据队列目前可用的饮食、生化和基因数据进行评估。拟议工作的结果将确定胆固醇吸收和合成的标志物与心血管疾病结果之间的关系；为胆固醇吸收和合成的测量建立参考值；并评估这些测量的预测价值，以确定相对于已确定的风险因素的高危个人。

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.