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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL104135-05
Application #
9250286
Study Section
Special Emphasis Panel (ZRG1-PSE-J (03)M)
Program Officer
Jaquish, Cashell E
Project Start
2016-06-30
Project End
2017-05-31
Budget Start
2016-06-30
Budget End
2017-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,713,047
Indirect Cost
$21,489
Name
University of Kentucky
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Aslibekyan, Stella; Agha, Golareh; Colicino, Elena et al. (2018) Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor ?. JAMA Cardiol 3:463-472
Ruhrmann, Sabrina; Ewing, Ewoud; Piket, Eliane et al. (2018) Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes. Mult Scler 24:1288-1300
Canty, Angelo J; Paterson, Andrew D (2018) Evidence of batch effects masking treatment effect in GAW20 methylation data. BMC Proc 12:32
Strickland, Justin C; Chen, I-Chen; Wang, Chanung et al. (2018) Longitudinal data methods for evaluating genome-by-epigenome interactions in families. BMC Genet 19:82
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Aslibekyan, Stella; Almasy, Laura; Province, Michael A et al. (2018) Data for GAW20: genome-wide DNA sequence variation and epigenome-wide DNA methylation before and after fenofibrate treatment in a family study of metabolic phenotypes. BMC Proc 12:35
Irvin, Marguerite R; Aslibekyan, Stella; Do, Anh et al. (2018) Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. Clin Epigenetics 10:56
Yusuf, Nabiha; Hidalgo, Bertha; Irvin, Marguerite R et al. (2017) An epigenome-wide association study of inflammatory response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. Pharmacogenomics 18:1333-1341
Aslibekyan, Stella; Irvin, Marguerite R; Hidalgo, Bertha A et al. (2017) Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). J Nutr Intermed Metab 8:1-7

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