Association between modifiable-lifestyle factors and DNA methylation: a discovery of biomarkers and links to cardiovascular outcomes Public
Do, Whitney (Spring 2021)
Published
Abstract
Epigenetics is the study of mitotically heritable changes in gene expression which do not cause changes to the underlying DNA sequence. Epigenetic mechanisms, including DNA methylation at cytosine and guanine nucleotide pair (CpG) sites, have been shown to be influenced by intrinsic (such as obesity and inflammation) and extrinsic (such as diet, physical activity and smoking) exposures serving as a link between an individual’s DNA and their environment. Examining DNA methylation in relation to modifiable-lifestyle risk factors may provide relevant information in several respects. As a molecular biomarker, DNA methylation could be useful in improving the detection of difficult to measure exposures or in the early detection of diseases. Additionally, as DNA methylation influences gene expression levels, it is important to examine the functional implications of these associations as they may have downstream effects on cardiometabolic health.
This dissertation project examined the association between differential DNA methylation with several modifiable-lifestyle exposures including diet quality, metabolic health and obesity. In Aim 1, we evaluated the association between diet quality as measured by the Alternative Healthy Eating Index-2010 (AHEI-2010) and the methylome using cross-sectional data from the Women’s Health Initiative (WHI) and the TwinsUK cohort. We discovered that diet quality was associated with widespread differential methylation patterns, with several of the replicated sites having been previously associated with obesity, inflammation, and dysglycemia. In Aim 2, we evaluated the relationship between body mass index (BMI) and differential DNA methylation in 17,034 participants from nine population based cohort studies. We discovered 1,238 CpG sites associated with BMI. Moreover, we found a unique methylomic profile of adiposity in individuals of African descent. In Aim 3, we examined whether BMI-associated methylation is influenced by metabolic health status. We found four CpG sites which may have a differential relationship with BMI in metabolically healthy vs. unhealthy individuals. These sites are located in several genes related to NF-kappa-B signaling suggesting that DNA methylation may differentially regulate obesity-associated inflammation by metabolic health status. Ultimately, this body of work will help to further our understanding of the molecular dysregulation caused by poor diet, metabolic abnormalities and obesity.
Table of Contents
CHAPTER 1 12
Introduction 12
CHAPTER 2 18
Background: Epigenetics in the study of lifestyle exposures 18
2.1 Diet and DNA methylation 19
2.2 Obesity and DNA methylation 22
Methods 23
Results 27
Discussion 31
References 35
Tables and Figures 43
CHAPTER 3 56
Methods 56
3.1 Study Population 56
3.2 Data Analyses 56
References 58
CHAPTER 4 59
Abstract 60
Background 61
Methods 62
Results 66
Discussion 68
References 73
Tables & Figures 78
CHAPTER 5 84
Introduction 84
Methods 85
Results 90
Discussion 91
References 95
Tables and Figures 98
CHAPTER 6 105
Abstract 105
Background 107
Methods 108
Results 113
Discussion 114
References 118
Tables and Figures 121
CHAPTER 7 129
References 136
About this Dissertation
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