Epigenetic Determinants of Lipid Response to Dietary Fat and Fenofibrate

膳食脂肪和非诺贝特脂质反应的表观遗传决定因素

• 批准号: 8509004
• 负责人: Donna K Arnett
• 金额: $ 92.44万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509004
• 关键词: Affect; Agonist; Alabama; Alleles; Alternative Splicing; Area; Atherosclerosis; Belief; Blood; CCL2 gene; Calories; Candidate Disease Gene; Cardiovascular Diseases; Cholesterol; Collaborations; Complex; DNA; DNA Methylation; Development; Diabetes Mellitus; Diet; Dietary Fats; Dyslipidemias; Eating; Environment; Environmental Risk Factor; Epidemic; Epigenetic Process; Family; Family Study; Family member; Fatty acid glycerol esters; Fenofibrate; Future; Gene Expression; Gene Structure; Genes; Genetic; Genetic Transcription; Genetic Variation; Glucose; Goals; Heart; Hispanics; Hypertriglyceridemia; IL6 gene; Individual; Inflammatory; Institutes; Insulin; Intake; Intervention; Intervention Studies; Knowledge; Lead; Lipids; Lipoproteins; Lymphocyte; Maps; Measures; Mediating; Messenger RNA; Metabolic syndrome; Methods; Methylation; MicroRNAs; Minnesota; Modeling; National Heart, Lung, and Blood Institute; Obesity; Participant; Particle Size; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Protocols documentation; Recruitment Activity; Relative (related person); Research; Resources; Role; Sampling; Scanning; T-Lymphocyte; TNF gene; Testing; Therapeutic; Triglyceride Metabolism; Triglycerides; Utah; Variant; Whole Blood; adiponectin; bisulfite; cardiovascular disorder risk; cohort; environmental intervention; epigenetic variation; epigenome; gene environment interaction; genetic pedigree; genome-wide; inflammatory marker; interest; lipid metabolism; member; next generation sequencing; novel; prevent; programs; promoter; public health relevance; research study; response; trait

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：血脂异常在心血管疾病的发生中起着很大的作用，这引起了人们的兴趣，以更好地理解负责血脂异常的环境因素，尤其是高甘油三酸酯血症。表观遗传变异可能影响甘油三酸酯（TG）代谢和对环境挑战的反应。我们的目标是进行第一个实验，以全面扫描表观基因组，以确保TG的决定因素和对两种“环境”干预措施的TG和其他血脂异常反应，一种是提高TGS（高脂餐），一个用于降低TGS（3周的Fenofibrate治疗）。这些实验将在基因环境相互作用网络“脂质降低和饮食的遗传学”（GOLDN）研究中进行的NHLBI计划（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，并将其广泛用于酶促和NMR脂质和炎症标记，以应对两种干预措施。 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非诺贝特治疗的背景。从这些结果中，我们将选择20个候选基因在AIM 2中进一步表征的最佳证据。（2）使用Bisulfite测序在所有1,048个家庭成员中使用亚硫酸盐测序来表征这20个基因的甲基化状态。 （3）在外部队列中复制AIM 1和2的重大发现。 （4）进行基因表达研究以确定目标1-3的甲基化发现的功能影响，因为DNA甲基化可能会以多种方式影响附近基因的表达，包括转录速率，替代剪接，microRNA抑制或等位基因特定表达。我们将使用一种称为RNASEQ的方法将下一代测序对150名受试者的mRNA和microRNA应用。如果成功的话，我们将确定新型的表观遗传变异，这些变化预测了对饮食脂肪反应不佳或对非诺贝型纤维化反应不佳的个体，这将导致靶向干预措施的发展，以更有效地预防和治疗高甘油三酸酯血症。