Epigenetic Determinants of Lipid Response to Dietary Fat and Fenofibrate

血脂异常在心血管疾病的发生中起着重要作用， 有兴趣更好地了解负责血脂异常的环境因素，特别是 高胆固醇血症表观遗传变异可能影响甘油三酯（TG）代谢， 应对环境挑战。我们的目标是进行首批实验， 全面扫描表观基因组，寻找TG和其他血脂异常反应的决定因素 两种“环境”干预，一种是提高TG（高脂肪餐），另一种是降低TG （3周非诺贝特治疗）。这些实验将在NHLBI计划中进行， 基因-环境相互作用网络的“降脂和饮食的遗传学”（GOLDN）研究。 GOLDN从明尼苏达州和犹他州的野外中心招募了家庭成员， 他们广泛用于酶和NMR脂质和炎症标志物，以响应 两次发言。拟议的研究将利用这一独特的资源， 收集样本以实现以下目的：（1）进行全基因组CpG甲基化 分析，使用下一代测序方法，特别是简化表示法 亚硫酸氢盐测序，来自184个家庭的1，048名个体，以确定表观遗传变异 促进TG和TG相关表型对脂肪餐、非诺贝特和 脂肪餐在非诺贝特治疗的背景下。从这些结果中，我们将选出20名候选人， 目的2中具有进一步表征的最佳证据的基因。(2)表征 使用启动子和其它区域的亚硫酸氢盐测序来检测这20个基因的甲基化状态 所有1,048名家庭成员(3)将目标1和2的重要结果复制到 外部队列。(4)进行基因表达研究，以确定 目的1-3的甲基化发现，因为DNA甲基化可能影响附近的 基因以各种方式，包括转录率，选择性剪接，microRNA 抑制或等位基因特异性表达。我们将对两者应用下一代测序 使用称为RNAseq的方法从150名受试者中提取mRNA和microRNA。如果成功，我们将 识别新的表观遗传变异，预测对膳食脂肪反应不良的个体， 有利的非诺贝特，这将导致有针对性的干预措施的发展， 有效预防和治疗高血脂症。

Dyslipidemias play a large role in the occurrence of cardiovascular disease, which has fueled interest to better understand environmental factors responsible for dyslipidemias, especially hypertriglyceridemia. Epigenetic variations may affect triglyceride (TG) metabolism and response to environmental challenges. Our goal is to conduct the first experiments that will comprehensively scan the epigenome for determinants of TG and other dyslipidemic responses to two “environmental” interventions, one to raise TGs (a high-fat meal), and one to lower TGs (3-week fenofibrate treatment). These experiments will be conducted in the NHLBI Program in Gene-Environment Interaction Network's “Genetics of Lipid Lowering and Diet” (GOLDN) study. GOLDN recruited family members from field centers in Minnesota and Utah and phenotyped them extensively for enzymatic and NMR lipids and inflammatory markers in response to the two interventions. The proposed study will build upon this unique resource using previously collected samples to implement the following aims: (1) Conduct genome-wide CpG methylation analysis, using next generation sequencing method, specifically, Reduced Representation Bisulfite Sequencing, in 1,048 individuals from 184 families to identify epigenetic variation contributing to the response of TGs and TG-related phenotypes to a fat meal, fenofibrate, and a fat meal in the context of fenofibrate treatment. From these results, we will select 20 candidate genes with the best evidence for further characterization in Aim 2. (2) Characterize the methylation state of these 20 genes using bisulfite sequencing of promoters and other regions of interest in all 1,048 family members. (3) Replicate significant findings from Aims 1 and 2 in external cohorts. (4) Conduct gene expression studies to identify the functional impact of methylation findings from Aims 1-3 since DNA methylation may affect the expression of nearby genes in a variety of ways, including transcription rates, alternative splicing, microRNA inhibition, or allele specific expression. We will apply next-generation sequencing to both mRNA and microRNA from 150 subjects using a method called RNAseq. If successful, we will identify novel epigenetic variations that predict individuals who respond poorly to dietary fat or favorably to fenofibrate which will lead to the development of targeted interventions to more effectively prevent and treat hypertriglyceridemia.