Genetic and Environmental Determinants of Triglycerides

描述(由申请人提供)： 高甘油三酯血症正在成为动脉粥样硬化的重要预测因子，最近的证据表明，甘油三酯(TGS)的相关表型，如甘油三酯残留颗粒和小颗粒低密度脂蛋白(LDL)，尤其是导致动脉粥样硬化的因素。TGS及其相关表型对环境的反应有相当大的差异。这项拟议研究的目的是描述TGS对两种环境的不同反应的遗传基础，一种是升高TGS(膳食脂肪)，另一种是降低TGS(非诺贝特治疗)。我们将在两个基因同质的中心(明尼阿波利斯和盐湖城)，从正在进行的NHLBI家庭心脏研究(FHS)的3代家系中招募2400名家庭成员。我们将收集饮食脂肪挑战前后的测量数据，以评估餐后TGS和相关的致动脉粥样硬化表型(极低密度脂蛋白TGS、乳胶粒TGS、TG残留颗粒、高密度脂蛋白和低密度脂蛋白颗粒大小、总胆固醇、低密度脂蛋白和高密度脂蛋白)。在TGS&gt；=130 mg/dl有2个或2个以上兄弟姐妹关系的家庭中，我们将在所有有意愿和符合条件的家庭成员中进行非诺贝特的短期、安慰剂对照、随机试验(预期样本量=1,200)。两个疗程的交叉设计将在两个为期三周的疗程(安慰剂或微粉化的非诺贝特，160毫克)之间进行为期两周的冲刷。大约1,000个家庭成员拥有一个马什菲尔德基因组标记集，作为NHLBI FHS的一部分；其余的1,400个将使用相同的标记集进行分型。我们将使用最先进的方法进行全基因组连锁分析，在脂肪负荷和非诺贝特治疗的背景下定位有助于甘油三酯反应的新遗传位点。我们将在10个候选基因中键入15个单核苷酸多态(SNPs)，这些基因已知有助于TGS对饮食脂肪和非诺贝特的反应，并为关联研究创建单倍型。我们将使用组合分割方法和神经网络来测试单个SNPs和单倍型与两种环境干预的响应之间的关联。识别在脂肪负荷和贝特治疗两种不同环境下预测甘油三酯反应的基因位点，可能为以下遗传途径提供洞察：(A)易患高甘油三酯血症，最终导致一级预防途径，以及(B)预测对降低甘油三酯的反应，导致治疗高甘油三酯血症的新药物靶点。

DESCRIPTION (provided by applicant): Hypertriglyceridemia is emerging as important predictor of atherosclerosis, and recent evidence suggests related phenotypes of triglycerides (TGs), such as TG remnant particles and small LDL particles, are particularly atherogenic. There is considerable variation in the response of TGs and related phenotypes to the environment. The aim of the proposed study is to characterize the genetic basis of the variable response of TGs to two environmental contexts, one that raises TGs (dietary fat), and one that lowers TGs (fenofibrate treatment). We will recruit 2,400 family members from 3-generational pedigrees of the ongoing NHLBI Family Heart Study (FHS) in two genetically homogeneous centers (Minneapolis and Salt Lake City). We will collect measurements before and after a dietary fat challenge to assess postprandial TGs and related atherogenic phenotypes (VLDL TGs, chylomicron TGs, TG remnant particles, HDL and LDL particle sizes, total cholesterol, LDL-C, and HDL-C). In families with 2 or more members in a sibship with TGs >= 130 mg/dl, we will conduct a short-term, placebo-controlled, randomized trial of fenofibrate in all willing and eligible family members (anticipated sample size = 1,200). A two-period crossover design will be executed with a 2-week washout between two 3-week treatment periods (placebo or micronized fenofibrate, 160 mg). About 1,000 family members have a Marshfield genome marker set available as part of NHLBI FHS; the remaining 1,400 will be typed using the same marker set. We will conduct genome-wide linkage analyses using state-of-the-art methods to localize novel genetic loci contributing to TG response in the context of fat loading and fenofibrate treatment. We will type 15 single nucleotide polymorphisms (SNPs) in ten candidate genes known to contribute to the response of TGs to dietary fat and fenofibrate, and create haplotypes for association studies. We will use combinatorial partitioning methods and neural networks to test association of the individual SNPs and haplotypes with response to the two environmental interventions. The identification of genetic loci that predict TG response in the presence of two disparate contexts, fat loading and fibrate therapy, may provide insights into genetic pathways (a) predisposing to hypertriglyceridemia, ultimately leading to avenues for primary prevention, and (b) predicting response to TG lowering, leading to new drug targets for hypertriglyceridemia.