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的测量来鉴定相对于已确定的风险因素处于发展心血管疾病（CVD）的高风险的个体的预测价值。具体目标是1）量化胆固醇稳态的循环指标[植物固醇和胆固醇水平（胆固醇吸收的替代措施）和胆固醇前体（胆固醇合成率的替代指标）]的血浆样本中，降低药物和对照组受试者的年龄，性别，体重指数，高血压和吸烟状况相匹配（n=330）; 2）通过以下方式评估在Frachial Offspring研究-周期6参与者中使用胆固醇稳态指标预测CVD风险的有效性：建立植物甾醇、胆甾烷醇和胆固醇前体的循环水平的成人正常范围（N=3378），B）确定植物甾醇、胆甾烷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）确定植物甾醇、胆甾烷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，胆固醇和胆固醇前体水平和选定的膳食摄入量数据（能量、蛋白质、脂肪、饱和脂肪酸、单不饱和脂肪酸、多不饱和脂肪酸和反式脂肪酸、胆固醇、纤维和抗氧化剂补充剂）和d）确定植物甾醇、胆甾烷醇和胆固醇前体水平与与CVD风险相关的选定基因型数据之间的关系（载脂蛋白E、载脂蛋白A-IV、清道夫受体B类1型[SRB 1]和ATP结合盒[ABC] G5和ABCG 8转运蛋白的基因位点）;和3）在整个10年期间监测Frachial Offspring研究队列中的临床事件（1995-2005），并将这些数据与植物甾醇、胆甾烷醇和胆固醇前体水平相关联。将首先在具体目标1中确定的受试者中量化胆固醇稳态指标，然后在具体目标2中确定的受试者中量化胆固醇稳态指标，由于开发了使用单个血浆样本的气相色谱法，现在可以实现平衡。这些数据将相对于队列目前可用的饮食、生化和基因型数据进行评估。拟议工作的结果将定义胆固醇吸收和合成的标志物与CVD结果之间的关系;建立胆固醇吸收和合成措施的参考值;并评估这些措施的预测价值，以确定相对于已建立的风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.