Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat

非诺贝特和膳食脂肪的脂质反应的全基因组关联研究

• 批准号: 9316688
• 负责人: Donna K Arnett
• 金额: $ 70.68万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316688
• 关键词: Age; Biological Assay; Biological Markers; Biological Models; Blood; Body Surface Area; Calcium-Activated Potassium Channel; Calories; Caucasians; Chemicals; Cholesterol; Data; Diet; Dietary Fats; Dietary Intervention; Disease; Drug Prescriptions; Drug Targeting; Dyslipidemias; Eating; Epigenetic Process; Family; Family Study; Fasting; Fatty Acids; Fatty acid glycerol esters; Fenofibrate; Fibrates; Funding; Genes; Genetic; Genome; Genomics; Goals; Heart; Hepatic; Hepatocyte; Heritability; Human; Hypertension; Hypertriglyceridemia; Ingestion; Institutes; Intervention; Link; Lipids; Lipoproteins; Mass Spectrum Analysis; Measurement; Measures; Metabolism; Methodology; Methylation; Modeling; Molecular; Myocardial Infarction; Nuclear; PPAR alpha; Participant; Pharmaceutical Preparations; Pharmacogenomics; Pharmacological Treatment; Phase; Phenotype; Phospholipids; Plasma; Population; Process; Protocols documentation; Recruitment Activity; Reporting; Research; Sample Size; Sampling; Signal Transduction; Sister; Site; Standardization; Steroids; Sterols; Stroke; Techniques; Testing; Therapeutic Intervention; Time; Triglycerides; United States National Institutes of Health; Universities; Validation; Variant; Washington; Work; base; blood lipid; cardiovascular disorder risk; density; disorder risk; epigenome-wide association studies; epigenomics; exome sequencing; gene environment interaction; genetic pedigree; genetic variant; genome wide association study; genome-wide; genomic data; improved; induced pluripotent stem cell; inter-individual variation; lipid I; lipid metabolism; member; metabolic profile; metabolomics; novel; personalized approach; prevent; programs; public health relevance; rare variant; response; sex; small molecule; tandem mass spectrometry; trait

 DESCRIPTION (provided by applicant): Dyslipidemias remain a critical determinant of cardiovascular disease risk. Effective dietary and therapeutic interventions to reduce dyslipidemia, including elevated triglycerides (TGs) and high non-HDL-cholesterol exist, yet there is much variation in lipid and lipoprotein level's response to these interventions. Genetics partially explain this variation. We hypothesize that, by using improved lipid phenotyping techniques, we will be able further characterize this interindividual variation of lipids in respone to diet and drug. Recent advances in mass spectrometry-based techniques allow metabolomic characterization in large populations. Detailed and precise measurement of lipid molecular species, a field known as "lipidomics," now offers an unprecedented picture of lipid metabolism. The Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study provides an ideal context in which to pursue this work. GOLDN is the largest family study conducted to date that has sought to identify genetic factors that explain response to two short-term interventions, one to raise lipids (i.e., ingestion of a high-fat meal, the "post-prandial lipemia" (PPL) intervention and one to lower lipids (i.e., treatment with fenofibrate (FFB)). The goal of the "Genomewide Association Study (GWAS) of Lipid Response to Fenofibrate and Dietary Fat" (Arnett, PI, R01-HL091357) was to identify the common genetic variants that explain response to the interventions. In addition to this, GOLDN is also conducting a genome- wide epigenomics study and exome sequencing through the NIH Pharmacogenomics Research Network (PGRN). The proposed work will leverage this wealth of genomic data in the context of state-of-the-art lipidomic phenotypes, specifically phospholipids, neutral lipids, and sterols, to identify rare and common variants and epigenetic marks that determine response to GOLDN's diet and drug interventions. Specifically, we aim to: (1) Quantify pre- and post-FFB treatment/PPL response of 350 metabolites. GOLDN recruited and examined 1048 Caucasians from 186 families. Participants were given an 83% fat meal and three weeks of FFB treatment, 250 mg/d. Blood was drawn at fasting and 6-hr post ingestion and again after 3 wk of FFB treatment. Plasma from each of these time points will be analyzed with for 350 lipidomic species. PPL response (estimated as the 6-hr TG response adjusted for baseline), and fenofibrate response (estimated by the ratio of post/pre TG values) of the new lipidomic phenotypes will be calculated. Responsive and heritable metabolites will be moved forward to Aim 2. (2) Test the association of these small molecules with (a) common (GWAS) and rare (WES) variants (b) methylation at CpG sites (EWAS). (3) Replicate PPL findings in 500 subjects selected from extremes of the PPL response in the HAPI Heart Study. (4) Use induced pluripotent stem cell- derived hepatocytes to functionally validate fenofibrate response variants identified in Aim 2. If successful, GOLDN will identify novel lipidomic biomarkers to predict efficacy and adverse responses to a high-fat meal and fenofibrate treatment, leading to more personalized approaches to diet and pharmacologic treatment.

 描述（由申请人提供）：血脂异常仍然是心血管疾病风险的关键决定因素。存在有效的饮食和治疗干预以降低血脂异常，包括升高的甘油三酯（TG）和高非HDL胆固醇，但脂质和脂蛋白水平对这些干预的反应存在很大差异。遗传学部分解释了这种变异。我们假设，通过使用改进的脂质表型分析技术，我们将能够进一步表征这种个体间的脂质变异，对饮食和药物的反应。基于质谱的技术的最新进展允许在大群体中进行代谢组学表征。脂质分子种类的详细而精确的测量，一个被称为"脂质组学"的领域，现在提供了一个前所未有的脂质代谢的图片。降脂药物和饮食网络（GOLDN）研究的遗传学为开展这项工作提供了理想的背景。GOLDN是迄今为止进行的最大的家庭研究，该研究试图确定解释对两种短期干预措施的反应的遗传因素，一种是提高血脂（即，摄入高脂肪膳食，"餐后脂血症"（PPL）干预和一种降低脂质（即，用非诺贝特（FFB）治疗）。"对非诺贝特和膳食脂肪的脂质反应的全基因组关联研究（GWAS）"（Arnett，PI，R01-HL 091357）的目的是确定解释对干预措施的反应的常见遗传变异。除此之外，GOLDN还通过NIH药物基因组学研究网络（PGRN）进行全基因组表观基因组学研究和外显子组测序。拟议的工作将在最先进的脂质组学表型，特别是磷脂，中性脂质和甾醇的背景下利用这一丰富的基因组数据，以鉴定罕见的和不常见的。 常见的变异和表观遗传标记，决定响应GOLDN的饮食和药物干预。具体而言，我们的目标是：（1）定量350种代谢物的FFB治疗/PPL反应前后。GOLDN招募并检查了来自186个家庭的1048名白人。参与者被给予83%的脂肪餐和三周的FFB治疗，250 mg/d。在空腹和进食后6小时抽血，并在FFB治疗3周后再次抽血。将分析这些时间点的血浆中的350种脂质组学物质。将计算新脂质组学表型的PPL反应（估计为针对基线校正的6小时TG反应）和非诺贝特反应（估计为TG后/前值的比值）。反应性和遗传性代谢物将移至目标2。(2)检测这些小分子与（a）常见（GWAS）和罕见（WES）变体（B）CpG位点甲基化（EWAS）的相关性。(3)从HAPI心脏研究中PPL反应的极端受试者中选择500例受试者，重复PPL结果。(4)使用诱导多能干细胞衍生的肝细胞功能验证目的2中鉴定的非诺贝特应答变体。如果成功，GOLDN将确定新的脂质组学生物标志物，以预测高脂餐和非诺贝特治疗的疗效和不良反应，从而实现更个性化的饮食和药物治疗方法。