Dyslipidemias play a large role in the occurrence of cardiovascular disease, which has fueledinterest to better understand environmental factors responsible for dyslipidemias, especiallyhypertriglyceridemia. Epigenetic variations may affect triglyceride (TG) metabolism andresponse to environmental challenges. Our goal is to conduct the first experiments that willcomprehensively scan the epigenome for determinants of TG and other dyslipidemic responsesto 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 inGene-Environment Interaction Network's ?Genetics of Lipid Lowering and Diet? (GOLDN) study.GOLDN recruited family members from field centers in Minnesota and Utah and phenotypedthem extensively for enzymatic and NMR lipids and inflammatory markers in response to thetwo interventions. The proposed study will build upon this unique resource using previouslycollected samples to implement the following aims: (1) Conduct genome-wide CpG methylationanalysis, using next generation sequencing method, specifically, Reduced RepresentationBisulfite Sequencing, in 1,048 individuals from 184 families to identify epigenetic variationcontributing to the response of TGs and TG-related phenotypes to a fat meal, fenofibrate, and afat meal in the context of fenofibrate treatment. From these results, we will select 20 candidategenes with the best evidence for further characterization in Aim 2. (2) Characterize themethylation state of these 20 genes using bisulfite sequencing of promoters and other regionsof interest in all 1,048 family members. (3) Replicate significant findings from Aims 1 and 2 inexternal cohorts. (4) Conduct gene expression studies to identify the functional impact ofmethylation findings from Aims 1-3 since DNA methylation may affect the expression of nearbygenes in a variety of ways, including transcription rates, alternative splicing, microRNAinhibition, or allele specific expression. We will apply next-generation sequencing to bothmRNA and microRNA from 150 subjects using a method called RNAseq. If successful, we willidentify novel epigenetic variations that predict individuals who respond poorly to dietary fat orfavorably to fenofibrate which will lead to the development of targeted interventions to moreeffectively prevent and treat hypertriglyceridemia.
Epigenetics is a relatively new area of study which seeks to understand how gene activity rather than genestructure influences people's traits. Epigenetic factors may explain why the levels of fat and cholesterol insome people's blood change dramatically after eating a high-fat meal or after taking fat-lowering drugs whilefat and cholesterol levels in other people change very little under the same conditions. This study aims todiscover the epigenetic factors that cause people's bodies to respond so differently to diet and drugs withthe belief that such knowledge could ultimately help lower people's risk for cardiovascular disease.
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