Obesity is associated with numerous comorbidities such cardiovascular diseases (CVD) and type 2 diabetes (T2D). The common denominator in the pathogenesis of the co-morbidities of obesity is the presence of an active, low-grade inflammatory process. In context of the recently emerging evidence on the importance of epigenetic regulation in the immune and inflammatory responses, we hypothesize that obesity induced defects in immune function is caused, at least in part, by DNA methylation changes in peripheral blood mononuclear cells in response to adipokines and cytokines secreted by adipose tissue. Based on our preliminary studies which provided strong support to this hypothesis, we aim to identify the differential methylation profiles between obese cases and lean controls and further evaluate whether these methylation changes are involved in the pathogenesis of obesity related co-morbidities. First, we will identify the CpG sites where DNA methylation differs between obese cases and lean controls employing a step-wise selection process involving 2 stages (Aim 1). After interrogation of 27,000 methylation sites in more than 14,000 genes in 100 obese cases and 100 lean controls, we will choose the most promising for validation in a subsequent stage with 300 obese cases and 300 lean controls eventually leading to the (approximately) 20 most likely/important sites. Next, we will determine the potential downstream mechanisms of DNA methylation differences on gene expression (Aim 2) by assessing whether changes in methylation of these CpG sites are associated with changes in gene expression in the cells collected from aim 1. Functional in vitro experiments will also be conducted to investigate whether demethylation of these CpG sites can activate gene expression. Furthermore, we will determine whether the effect of obesity on CVD and T2D risk factors is -at least partially- mediated by the methylation changes of these CpG sites in a total of 1600 subjects (Aim 3). Secondary specific aims will test (1) whether the above relationships are ethnicity and/or gender dependent;(2) whether 8-month aerobic exercise intervention in overweight children will change the methylation status of these differential methylation sites. Identification of methylation changes in specific genes in obesity will provide important targets for further study into the mechanisms of obesity's effect on the immune system and the potential to develop new therapies to treat multiple obesity comorbidities independent of weight loss.

Public Health Relevance

Obesity is becoming a global epidemic in both children and adults. Obesity dramatically increases the risk of many diseases such as cardiovascular disease and type 2 diabetes.
This research aims to identify obesity induced epigenetic changes in the immune and inflammatory response and further evaluate whether these changes are associated with the risk of cardiovascular disease and type 2 diabetes. The identification of epigenetic changes in specific genes in obesity will provide important targets for developing new prevention approaches or therapies to treat multiple obesity co-morbidities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL105689-01
Application #
8023366
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Papanicolaou, George
Project Start
2011-07-01
Project End
2015-12-31
Budget Start
2011-07-01
Budget End
2011-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$594,795
Indirect Cost
Name
Georgia Regents University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Wang, Xiaoling; Pan, Yue; Zhu, Haidong et al. (2018) An epigenome-wide study of obesity in African American youth and young adults: novel findings, replication in neutrophils, and relationship with gene expression. Clin Epigenetics 10:3
Hao, G; Wang, X; Treiber, F A et al. (2018) Body mass index trajectories in childhood is predictive of cardiovascular risk: results from the 23-year longitudinal Georgia Stress and Heart study. Int J Obes (Lond) 42:923-925
Chen, Li; Dong, Yanbin; Wang, Xiaoling et al. (2018) Epigenome-Wide Association Study of Dietary Fiber Intake in African American Adolescents. Mol Nutr Food Res 62:e1800155
Xu, Yiming; Wang, Yong; Yan, Siyuan et al. (2017) Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis. EMBO Mol Med 9:1263-1278
Wang, Xiaoling; Snieder, Harold (2017) Assessing genetic risk of hypertension at an early age: future research directions. Expert Rev Cardiovasc Ther 15:809-812
Wu, Jiazhu; Xu, Xiaojing; Lee, Eun-Joon et al. (2016) Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. Oncotarget 7:40558-40570
Ye, Chengcheng; Pan, Yue; Xu, Xiaojing et al. (2016) Pulse wave velocity in elastic and muscular arteries: tracking stability and association with anthropometric and hemodynamic measurements. Hypertens Res 39:786-791
Wang, Xiaoling; Xu, Xiaojing; Su, Shaoyong et al. (2015) Familial aggregation and childhood blood pressure. Curr Hypertens Rep 17:509
Küpers, Leanne K; Xu, Xiaojing; Jankipersadsing, Soesma A et al. (2015) DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. Int J Epidemiol 44:1224-37
Zhou, Hongyi; Lei, Xinnuo; Benson, Tyler et al. (2015) Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals. J Lipid Res 56:1912-25

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