Genetic and Environmental Determinants of Triglycerides

描述（由申请人提供）： 高甘油三酯血症是动脉粥样硬化的重要预测因子，最近的证据表明甘油三酯（TG）的相关表型，如TG残留颗粒和小LDL颗粒，特别是动脉粥样硬化。TG和相关表型对环境的反应存在相当大的差异。拟议的研究的目的是表征TG对两种环境背景的可变反应的遗传基础，一种是提高TG（膳食脂肪），另一种是降低TG（非诺贝特治疗）。我们将从两个遗传同质中心（明尼阿波利斯和湖城）正在进行的NHLBI家庭心脏研究（FHS）的3代家系中招募2,400名家庭成员。 我们将在膳食脂肪挑战前后收集测量值，以评估餐后TG和相关致动脉粥样硬化表型（VLDL TG、乳糜微粒TG、TG残留颗粒、HDL和LDL颗粒大小、总胆固醇、LDL-C和HDL-C）。在TG ≥ 130 mg/dl的同胞中有2名或2名以上成员的家庭中，我们将在所有自愿且符合条件的家庭成员中进行一项短期、安慰剂对照、非诺贝特随机试验（预期样本量= 1，200）。将执行两个阶段交叉设计，两个3周治疗阶段之间有2周洗脱期（安慰剂或微粉化非诺贝特，160 mg）。 大约1,000个家庭成员有一个马什菲尔德基因组标记集，作为NHLBI FHS的一部分;其余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，以定位在脂肪负荷和非诺贝特治疗背景下有助于TG反应的新遗传位点。我们将在10个已知与TG对膳食脂肪和非诺贝特的反应有关的候选基因中确定15个单核苷酸多态性（SNPs），并为关联研究创建单倍型。我们将使用组合分区方法和神经网络来测试个体SNP和单倍型与对两种环境干预的响应之间的关联。 在两种不同的情况下，脂肪负荷和贝特类药物治疗，预测TG反应的遗传基因座的鉴定，可能会提供对遗传途径的见解（a）诱发高血脂症，最终导致一级预防的途径，和（B）预测对TG降低的反应，导致高血脂症的新药物靶点。

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.